Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institute on Aging (NIA), (

Components of Participating Organizations
National Institute on Aging (NIA), (

Title:  Vulnerable Dendrites and Synapses in Aging and Alzheimer’s Disease (R01)

Announcement Type

Program Announcement (PA) Number: PA-09-061

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through ( using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide. 


This FOA must be read in conjunction with the application guidelines included with this announcement in for Grants (hereafter called

A registration process is necessary before submission and applicants are highly encouraged to start the process at least four (4) weeks prior to the grant submission date. See Section IV.

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Catalog of Federal Domestic Assistance Number(s)

Key Dates
Release/Posted Date: December 18, 2008
Opening Date:  January 5, 2009 (Earliest date an application may be submitted to
Letters of Intent Receipt Date(s): Not Required
NOTE: On-time submission requires that applications be successfully submitted to no later than 5:00 p.m. local time (of the applicant institution/organization). 
Application Due Date(s):  Standard dates apply, please see  
AIDS Application Due Date(s): Standard dates apply, please see
Peer Review Date(s): Standard dates apply, please see 
Council Review Date(s): Standard dates apply, please see
Earliest Anticipated Start Date(s): Standard dates apply, please see
Additional Information To Be Available Date (URL Activation Date): Not Applicable
Expiration Date: January 8, 2012

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Purpose. This FOA issued by the National Institute on Aging (NIA) invites applications for the study of factors regulating neuroplasticity with a particular emphasis on the age-dependent changes in the functions of dendrites, spines and synapses of key cell types in regions of brain especially vulnerable in Alzheimer’s disease (AD), and in models (in vitro and in vivo) of aging and of AD.   Neuroplasticity refers to the changes in both structure and function of the brain that occur in response to experiential stimuli.  This ability of the brain to reorganize itself is critical both in normal development and learning, and it is no less important in aging and neurodegenerative disorders.

The decline of cognitive functions in aging and disease, especially those functions that rely upon the medial temporal lobe and prefrontal cortex, appears to stem, at least in part, from selective changes in synaptic function and integrity.  This initiative solicits research to investigate the factors regulating synaptic plasticity and dysfunction and selective neuronal vulnerability with aging and in certain neurodegenerative disorders such as AD using in vitro and in vivo models.

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
2. Cost Sharing or Matching
3. Other-Special Eligibility Criteria

Section IV. Application and Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
    A. Submission, Review, and Anticipated Start Dates
          1. Letter of Intent
    B. Submitting an Application Electronically to the NIH
    C. Application Processing   
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements and Information

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting

Section VII. Agency Contacts
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Alzheimer’s disease (AD) is the most common cause of dementia among people age 65 and older.  In AD, cortical atrophy begins in the medial temporal lobe progressing to a global atrophy by end stage.  There is as yet no satisfactory explanation for the selective vulnerability of circuits affected early in AD or for its spread.  As some people grow older they experience memory problems. Memory impairment, beyond that expected for one’s age, can presage AD.  There are several types of mild cognitive impairment (MCI) based upon the underlying cause and the aspects of cognition most affected. “Amnestic MCI,” also referred to as MCI with memory loss, is the subtype most likely to lead to AD.  For those in whom MCI does progress, the ability to learn new information is lost to a disease process that worsens with time.  Fluctuation of the earliest amnestic symptoms suggests that subtle and, possibly, intermittent changes interrupt functions at the synapse.

Likewise brain aging is often associated with impairments in learning and memory; further, it shares features similar to those caused by injury to the hippocampus.  Such changes may contribute to regionally selective age-related cognitive changes.  It has been shown that many aged rats have deficits of spatial memory, and that spatial memory depends upon an intact hippocampus.   Comparing the spatial firing patterns of CA1 (graded response type) and CA3 (all or none response type) neurons in aged memory-impaired rats with those of young rats exploring either novel or familiar environments revealed that there were no differences between CA1 “pyramidal neurons that fire strongly when a freely behaving rat occupies particular locations in an environment (place cells) in young and old rats (Wilson et al., 2005).  However, CA3 place cells in aged animals generally had higher firing rates and failed to modulate those firing rates and place fields compared with those of young rats introduced into a novel environment.  That failure appeared to limit processing and encoding of new information received from the entorhinal cortex.  These data suggest that dysfunction of the CA3 subregion of hippocampus may contribute to selective age-related spatial memory impairment.

The purpose of this initiative is to solicit research proposals that will investigate the factors regulating synaptic plasticity and dysfunction with a particular emphasis on the age-dependent changes in the functions of dendrites, spines and synapses of key cell types in regions of brain that are selectively vulnerable in certain neurodegenerative disorders such as AD, or with aging using, for example, in vitro and in vivo models.

Some animal studies have suggested that age-related cognitive decline and AD reflect vulnerability of the same circuits.  Generally, the loss of neurons as a function of age does not explain age-related cognitive decline.  While neuronal cell death predominates in later stages of AD, age-related cognitive impairments and cognitive impairment early in the course of AD likely reflect more subtle alterations in the synapses of otherwise intact circuits.  One possibility is that regionally specific changes in the branching of dendrites, the density of spines, the polyribosome complexes contained within them, synaptic receptor levels, and the influence of glia on neurons may be more indicative of the effects that aging and age-associated diseases exert on the structure and function of the nervous system.  Translation of dendritic mRNAs contributes to the persistent, activity-dependent changes at individual synapses; the best known of these are referred to as long-term potentiation (LTP) and long-term depression (LTD).   These operationally defined models of synaptic behavior, too, can serve to provide a context within which changes observed in age- and disease- associated pathologies can be better understood.

Comparisons of patients with AD to age-matched control individuals showed that the density of neocortical synapses correlated strongly with neuropsychological and neurochemical measures and that continued loss of specific synaptic connections was the likely basis for the progression of Alzheimer’s disease (De Kosky et al. 1990; Terry et al. 1991; Sze et al. 1997; and Scheff et al., 2006). 

Early work (1977-1986) using electron microscopy, especially that done by Geinisman and colleagues, had shown that the functional decline or partial deafferentation of granule cells in the molecular layer of the dentate gyrus (DG) observed in the aged rat was caused not by the loss of neurons but by a reduction in the number, volume fraction, and surface area of dendritic shaft profiles – dendritic atrophy.  Using unbiased stereology Geinisman et al. (1992) also demonstrated that the number of dendritic spines per postsynaptic neuron was decreased in the DG, and that the loss involved perforated axospinous, but not axodendritic, synapses of the DG molecular layer.  The reduction in synapse number correlated with spatial memory deficits in aged rats.  More recently, it has been suggested that for aged, learning-impaired rats cognitive decline may develop as a consequence of hippocampal synapses being “silenced” or becoming non-functional (Burke and Barnes, 2006).

Synapse loss is particularly relevant because it tracks closely with the extent of early cognitive impairment rather than with any other clinical signs of brain injury.  Defects in dendritic spines appear to be common to several forms of cognitive deficits, including mental retardation and AD (Zhao et a., 2005).  In a number of different animal models of AD (Lanz et al., 2003; Moolman et al., 2004; Spires et al., 2005 and Oakley et al., 2006), it has been shown there are changes in dendrites and dendritic spines as a function of beta-amyloid (Aβ) plaque development.  A study (Saura et al., 2005) that used a line of amyloid precursor protein (APP) transgenic mice (J20) crossed to presenilin-1 conditional knockout mice (cKO/tg) revealed that partial inactivation of presenilin 1 (PS1) gene, which plays an essential role in γ–secretase cleavage of APP and the release of Aβ peptides, eliminated the development of amyloid plaques in 6 month old animals, and in young cKO/tg mice (at 3 months of age) rescued contextual and spatial learning and memory deficits.  PS1 inactivation in the older cohort of cKO/tg mice failed to rescue the memory and hippocampal synaptic deficits.  This is one of a number of examples of the modulation of Ab levels reversing cognitive deficits only early in the development of pathology but not later.  Ohno et al., (2006) in experiments that used an APP/PS1 transgenic line crossed to BACE (β-site APP cleaving enzyme) knockout mice, resulting in mice which lack the enzymes needed to make Aβ, demonstrated the rescue of a behavior that was dependent upon an intact hippocampus. Because elevated levels of soluble Aβ oligomers, peptide fragments of APP enzymatically cleaved from its membrane-spanning region that may play a role in the memory decline observed in AD, were also reduced in these mice, it was suggested that Aβ oligomers might be responsible for the observed behavioral deficits.  More recently, Shankar et al. (2008) provided evidence that soluble Aβ, isolated from the cerebral cortex of humans with AD, inhibited long-term potentiation, enhanced long-term depression, and reduced spine density along dendrites in rodent hippocampus.

In transgenic mouse models of AD, spine density in the outer molecular layer of the dentate gyrus and LTP decrease well before a measurable rise of insoluble Aβ and any evidence of amyloid plaque formation (Jacobsen et al., 2006).   At present, the mechanism(s) through which these changes are effected are not known.  One hypothesis (Selkoe, 2002) suggests that AD “begins with subtle alterations of hippocampal synaptic efficacy prior to frank neurodegeneration, and that synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.”  Under this rubric, Aβ might affect synapses intra-neuronally through, for example, the Fyn kinase pathway (Chin et al., 2004), or extracellular soluble forms of Aβ called ADDLs (amyloid beta-derived diffusible ligands) might affect dendrites and spines by specific receptor-mediated binding (Lacor et al, 2004) involving, possibly, the p21-activated pathway.

With respect to extracellular pathways, using human tissue (normal and AD) and mouse (APPswe transgenic mice) and rat neurons in culture, Zhao et al., (2006) provided data showing that defects in dendritic spine PAK pathway signaling (p21-activated kinase) led to cofilin pathology, significant drebrin loss and memory deficits like those observed in AD and Down syndrome.  Normal functioning of cofilin is essential for the maintenance of actin dynamics.  Intracellular inclusion bodies containing actin rods and other actin-binding proteins (Hirano bodies) are prominent in the hippocampus and cortex in AD.  pPAK and cofilin pathologies along with the loss of postsynaptic drebrin – a protein localized at spines - suggested to Cole and colleagues that defects in this actin-regulatory machinery could underlie the dendritic and synaptic dysfunction in AD (Zhao et al., 2006).  PAK is a serine/threonine kinase, which is involved in regulating spine actin assembly and disassembly and spine morphogenesis, that promotes neurite outgrowth.  Strengthening the argument that dendritic spine defects play a critical role in the cognitive decline in AD, dendritic postsynaptic proteins of excitatory neurons are reduced by 70-95% while neuronal losses are estimated to be from 5-40% during the progression of AD.  PAK inhibition resulting in drebrin and cofilin pathologies and behavioral deficits may be Ab-induced.  For example, in their study of Aβ1-42 oligomer-treated primary cultures of rat (E-18) hippocampal neurons, there was a rapid and persistent reduction of PAK activity (Zhao et al., 2006).  Aβ oligomers (or ADDLs) may specifically bind to PSD-95-positive excitatory synapses.  This might be one mechanism – a selective attack - whereby particular synapses are targeted in cognitive decline and AD.

In an in vitro study, hippocampal neurons derived from amyloid precursor protein (APP) knock out mice have an increased number of functional synapses – both the amplitude and frequency of excitatory synaptic currents are increased - suggesting that synapse formation and function are diminished by APP or its metabolites (Priller et al.,2006).  Additional evidence suggests that in neurons from Tg2576 transgenic mice iintraneuronal accumulation of Aβ impairs multivesicular body (late endosomes) trafficking by inhibiting the ubiquitin-proteasome system (Almeida et al., 2006).  That inhibition, in turn, may impair endocytic trafficking and sorting of neuronal receptors and may be another way in which Aβ is linked to synaptic dysfunction in AD.

The effect of aberrant APP metabolism can have widespread network effects. In APP23 transgenic mice there is no age-related loss of neocortical synaptophysin-positive presynaptic terminals despite progressive amyloid deposition and there are no significant changes apparent in the locus ceruleus (LC), an aminergic brain stem nucleus.  Heneka et al., (2006) using APP23 transgenic mice treated with the selective alkylating neurotoxin, dsp4, (which lesions the majority of noradrenergic neurons originating in the LC) observed that degeneration of LC affects morphology, metabolism, and function of amyloid plaque containing LC projection areas in these mice.  The loss of noradrenergic innervation of LC projection areas resulted in enhanced Ab plaque formation, increased neurodegeneration (loss of cholinergic boutons) and neuronal cell loss in frontal cortex and in CA1 and CA2 of the hippocampus – areas never affected by the application of the neurotoxin in non-transgenic mice.

In other work, the loss of dendrites in APP23 transgenic mice (at 3-,5-, 11- , and 15-months of age) was directly examined using retrograde DiI tracing which results in precise, Golgi-like tracing of neurons in post-mortem fixed tissue (Capetillo-Zarate et al, 2006).  In AD the pyramidal neurons of layers III and V are vulnerable.  Layer III commissural neurons within the contralateral frontocentral cortex labeled by DiI tracer were examined in the primary and secondary motor cortex and the somatosensory cortex.  Their analyses showed that Ab induced a progressive degeneration of morphologically distinct types of commissural neurons in layer III of frontocentral cortex.  For two of the three neuron classes examined, cell numbers declined and the dendritic trees of the neurons that remained were diminished in size as the concentration of oligomeric Aβ increased with age.  Given the large surface area of the dendritic tree especially of the type I commissural neurons, it was suggested that the effects of exposure to Ab-aggregates on the arbor contributes to progressive neuronal vulnerability.

Apolipoprotein E is a small secreted glycoprotein that transports lipoproteins, cholesterol, phospholipids and mediates uptake of the bound particles into target cells by receptor-mediated endocytosis.  Not only is the APOE e4 allele a well-accepted genetic risk factor for AD but the three APOE alleles are differentially involved in repair and regeneration following brain injury as well as in neurite sprouting.  At least with respect to CA1 parvalbulmin-positive GABAergic hippocampal neurons, there is evidence from a study of age-matched non-demented individuals having different APOE genotypes suggesting that apolipoprotein E isoforms do not modulate the initial formation of dendrites (Schönheit et al., 2006).  Parvalbumin-positive neurons do not form tangles or neuropil threads but their dendrites are reduced late in the course of AD following deafferentation. The results of that analysis support the notion that apolipoprotein E exerts its influence on the shape and extent of the dendritic arbor after some “plastic” challenge rather than there having been an influence of the gene product early on in development.  A recent report (Jiang et al, 2008) has suggested that ApoE subtypes have a role in but vary in their capability to facilitate the enzymatic degradation of Aβ and its clearance from brain.

If the Aβ peptide has a part in the development of AD it may not act alone. Aβ (oligomeric species and plaque) along with tau are the hallmark lesions of AD.  Over a decade ago certain mutations in the gene encoding the microtubule-associated protein tau, expressed in neurons, were shown to cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), one of the dis-orders associated with frontotemporal lobar degeneration.  Some of the features of the class of disorders known collectively as tauopathies - Alzheimer’s disease and Pick disease are two others - involve hyperphosphorylation, mislocalization and pathological conformation of tau protein – a microtubule associated phosphoprotein.   Given neurons’ polarity, numerous dendrites and, sometimes, quite long axons, the intracellular transport of cargoes of various types along microtubules is a challenge for neurons but it is essential if proper neuronal function is to be maintained.  Dysfunction or failure of “axonal transport” may play a role in neurodegenerative disease.  Mandelkow and collaborators (Eckermann et al., 2007 and Mocanu et al., 2008) reported on the development of two transgenic mouse lines based on the regulated expression in forebrain of the four-repeat domain of human tau with which to gauge the impact of tau toxicity in neurons.  Both lines of mice expressed tau at low levels, and the hexapeptide motifs appear to drive the formation of paired helical filaments.  One of these inducible models carried a truncated tau gene (∆K280) like that found in a single case of FTDP-17 and was tau-aggregation-prone; the other model that carried the same ∆K280 mutation but with two additional proline mutations, one in each of the two hexapeptide motifs, was tau-aggregation-resistant as the proline residues disrupt b-structure.  In both lines of mice there is mislocalization and hyperphosphorylation of tau protein.  However, in the aggregation-prone mutant there was a marked astrogliosis and a decrease in the numbers of dentate gyrus neurons, and in CA1 the density of spines and synapses was 27% less than that of either control or tau-aggregation-resistant mice after 5 months of transgene expression.  With respect to the protein tau and protein/organelle motility within axons and dendrites, much remains to be discovered.  Not only will it be important to determine how mutations or post-translational modifications affect functions related to trafficking during the course of normal aging but also how changes in the cytoskeleton impact the function of synapses in neurodegenerative diseases.

In addition to meeting all of the demands of the neuronal soma with respect to molecules both large and small, gene expression in neurons involves the delivery of mRNAs to particular subcellular domains via particular transport mechanisms in axons and dendrites where translation of those mRNAs can be locally controlled.  Local protein synthesis and the degradation of proteins within dendrites play a critical role in activity-dependent change at the synapse. It has been estimated that approximately 25% of spine synapses contain the “machinery” needed for protein synthesis although the prevalence of synapse-associated ribosomes and polyribosomes varies by neuron type and across development. 

In a review by Steward and Schuman (2003), a limited number (thus far) of mRNAs appear to be localized in dendrites facilitating their analysis.  Selective localization of the machinery for protein synthesis, both pre- and post- synaptically, makes regulation of translation of particular proteins by synaptic signals possible.  Protein translation independent of the neuronal soma may have important implications for the relative autonomy of dendrites in synaptic responsiveness and plasticity (Barrett et al., 2006).  The availability of ribosomes at the synapse may be rate-limiting, affecting the extent to which alterations in initiation factors (signaling through the synapse) could affect the translational capacity in dendrites.  The misregulation of protein synthesis-dependent plasticity in particular synapses could contribute to cognitive decline and to neurological disorders.

Potential research topics include the following subjects, but research grant applications received in response to this announcement need not be limited to these subjects. It should be emphasized that in most of the suggestions below, applications responsive to the FOA could involve a focus on either aging or Alzheimer’s disease (or both).

Citations for this section on research objectives can be found at

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism of Support

This FOA will use the R01 award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.  

This FOA uses “Just-in-Time” information concepts (see SF424 (R&R) Application Guide). It also uses the modular as well as the non-modular budget formats (see Specifically, a U.S. organization submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs) should use the PHS398 Modular Budget component.

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component.

2. Funds Available

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds.

Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

1.B. Eligible Individuals

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application for projects that require a “team science” approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at All PDs/PIs must be registered in the NIH electronic Research Administration (eRA) Commons prior to the submission of the application (see for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. The NIH review criteria for approach, investigators, and environment have been modified to accommodate applications involving either a single PD/PI or multiple PDs/PIs. When considering the multiple PD/PI option, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application.  Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

3. Other-Special Eligibility Criteria

Number of Applications. Applicants may submit more than one application, provided that each application is scientifically distinct.

Resubmissions. Applicants may submit a resubmission application, but such an application must include an “Introduction” addressing the issues that were raised in the previous critique (Summary Statement). Beginning with applications intended for the January 25, 2009 official submission due date, all original new applications (i.e., never submitted) and competing renewal applications will be permitted only a single amendment (A1).  See and NOT-OD-09-016   Original new and competing renewal applications that were submitted prior to January 25, 2009 will be permitted two amendments (A1 and A2).  For these “grandfathered” applications, NIH expects that any A2 will be submitted no later than January 7, 2011, and NIH will not accept A2 applications after that date.

Renewals. Applicants may submit a renewal application.

Section IV. Application and Submission Information

To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, use the “Apply for Grant Electronically” button in this FOA or link to and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

PDs/PIs should work with their institutions/organizations to make sure they are registered in the NIH eRA Commons.

Several additional separate actions are required before an applicant can submit an electronic application, as follows:  

1) Organizational/Institutional Registration in Registered  

2) Organizational/Institutional Registration in the eRA Commons

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

Both the PD(s)/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

Note: If a PD/PI is also an NIH peer-reviewer, the DUNS number obtained and used in the reviewer role may NOT be used for, and is not applicable to, any Grant Application to the Federal Government. This individual DUNS number is different from the DUNS number used by the applicant organization. The individual DUNS number should be used only for the purposes of personal reimbursement.

Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and the SF424 (R&R) Application Guide for this FOA through

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

For further assistance, contact GrantsInfo -- Telephone 301-435-0714, Email:

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide for this FOA through

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. Some fields within the SF424 (R&R) application components, although not marked as mandatory, are required by NIH (e.g., the “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”

The SF424 (R&R) application has several components. Some components are required, others are optional. The forms package associated with this FOA in includes all applicable components, required and optional. A completed application in response to this FOA includes the data in the following components:

Required Components:

SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist

PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6., “Special Instructions,” regarding appropriate required budget component.)

Optional Components:

PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form

Foreign Organizations (Non-domestic [non-U.S.] Entities)

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at:

Applications from Foreign organizations must:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States (U.S.) or that augment existing U.S. resources.


Applications with Multiple PDs/PIs

When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the "Contact” PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.

Information for the Contact PD/PI should be entered in item 15 of the SF424 (R&R) Cover component. All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of “PD/PI.” Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the “Credential” field of the Research & Related Senior/Key Person component. Failure to include this data field will cause the application to be rejected.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled “Multiple PD/PI Leadership Plan” [Section 14 of the Research Plan Component in the SF424 (R&R)], must be included. A rationale for choosing a multiple PD/PI approach should be described.  The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators. 

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan.  In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award (NoA).

Applications Involving a Single Institution

When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions 

When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget component. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form. 

When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only. Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 5.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.

3. Submission Dates and Times

See Section IV.3.A. for details.

3.A. Submission, Review, and Anticipated Start Dates

Opening Date:  January 5, 2009. (Earliest date an application may be submitted to
Letter of Intent Receipt Date(s):Not Applicable 
Application Due Date(s):  Standard dates apply, please see
AIDS Application Due Date(s): Standard dates apply, please see
Peer Review Date(s): Standard dates apply, please see
Council Review Date(s): Standard dates apply, please see
Earliest Anticipated Start Date(s): Standard dates apply, please see  

3.A.1. Letter of Intent

A letter of intent is not required for the funding opportunity.

3.B. Submitting an Application Electronically to the NIH

To submit an application in response to this FOA, applicants should access this FOA via and follow Steps 1-4. Note:  Applications must only be submitted electronically.  PAPER APPLICATIONS WILL NOT BE ACCEPTED. 

3.C. Application Processing

Applications may be submitted on or after the opening date and must be successfully received by no later than 5:00 p.m. local time (of the applicant institution/organization) on the application due date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the due date(s) and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully submitted through, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two weekdays (Monday – Friday, excluding Federal holidays) to view the application image to determine if any further action is necessary.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete applications will not be reviewed.

There will be an acknowledgement of receipt of applications from and the Commons. The submitting AOR/SO receives the acknowledgments. The AOR/SO and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific Review Group is also in the Commons. 

Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on their application status in the Commons.

The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. However, the NIH will accept a resubmission application, but such application must include an Introduction addressing the critique from the previous review.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or renewal award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or renewal award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement

6. Other Submission Requirements and Information.

PD/PI Credential (e.g., Agency Login)

The NIH requires the PD(s)/PI(s) to fill in his/her Commons User ID in the “PROFILE – Project Director/Principal Investigator” section, “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component.

Organizational DUNS

The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”

PHS398 Research Plan Component Sections

Page limitations of the PHS398 Research Plan component must be followed as outlined in the SF424 (R&R) Application Guide. While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.   

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts.

Specific Instructions for Applications Requesting $500,000 (direct costs) or More per Year

Applicants requesting $500,000 or more in direct costs for any year (excluding consortium F&A costs)  must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as plans are being developed for the study;

2) Obtain agreement from the IC staff that the IC will accept the application for consideration for award; and,

3) Include a cover letter with the application that identifies the staff member and IC who agreed to accept assignment of the application.

This policy applies to all new, renewal, revision, or resubmission applications. See NOT-OD-02-004, October 16, 2001.

Appendix Materials 

Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not comply with the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of the research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in the Resource Sharing section of the application (see

(a) Data Sharing Plan: Regardless of the amount requested, investigators are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact (see Data-Sharing Policy or

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources or state appropriate reasons why such sharing is restricted or not possible (see Sharing Model Organisms Policy, and NOT-OD-04-042.)

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible.  A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (e.g., blood pressure or weight) or the presence or absence of a disease or condition.  For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (go to NOT-OD-07-088, and

Foreign Applications (Non-domestic [non-U.S.] Entities)

Indicate how the proposed project has specific relevance to the mission and objectives of the NIH/IC and has the potential for significantly advancing the health sciences in the United States.

Section V. Application Review Information

1. Criteria 

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications submitted for this funding opportunity will be assigned on the basis of established PHS referral guidelines to the ICs for funding consideration.

Applications that are complete will be evaluated for scientific and technical merit by (an) appropriate scientific review group(s) in accordance with NIH peer review procedures ( using the review criteria stated below.  

As part of the scientific peer review, all applications will:

Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability.  As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system. 

Overall Impact. Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following five core review criteria, and additional review criteria (as applicable for the project proposed). 

Core Review Criteria.  Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each.  An application does not need to be strong in all categories to be judged likely to have major scientific impact.  For example, a project that by its nature is not innovative may be essential to advance a field.

Significance.  Does the project address an important problem or a critical barrier to progress in the field?  If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved?  How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s).  Are the PD/PIs, collaborators, and other researchers well suited to the project?  If Early Stage Investigators or New Investigators, do they have appropriate experience and training?  If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)?  If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation.  Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions?  Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense?  Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach.  Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project?  Are potential problems, alternative strategies, and benchmarks for success presented?   If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment.  Will the scientific environment in which the work will be done contribute to the probability of success?  Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed?  Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? 

Additional Review Criteria.  As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

Protections for Human Subjects.  For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects  and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials.

Inclusion of Women and Minorities. When the proposed project involves clinical research the committee will evaluate the proposed plans for inclusion of minorities and members of both genders.

Vertebrate Animals.  The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia.

Resubmission Applications.  When reviewing a Resubmission application (formerly called an amended application), the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewal Applications.  When reviewing a Renewal application (formerly called a competing continuation application), the committee will consider the progress made in the last funding period.

Biohazards.  Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Additional Review Considerations.  As applicable for the project proposed, reviewers will address each of the following items, but will not give scores for these items and should not consider them in providing an overall impact score.

Budget and Period Support.  Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Select Agent Research. Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Applications from Foreign Organizations.  Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Resource Sharing Plans.  Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan Data-Sharing Policy or Sharing Model Organisms Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.and 3) Genome Wide Association Studies (GWAS) NIH Guide NOT-OD-07-088, and

3. Anticipated Announcement and Award Dates

 Not Applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the NIH eRA Commons

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Section IV.5., “Funding Restrictions.”       

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research (program), peer review, and financial or grants management issues:

1. Scientific/Research Contact(s):

D. Stephen Snyder, Ph.D.
Division of Neuroscience
National Institute on Aging
Gateway Building, Room 350

7201 Wisconsin Avenue
Bethesda, MD 20892-9205
Telephone: (301) 496-9350
Fax: (301) 496-1494

2. Peer Review Contact(s):

Not Applicable

3. Financial/Grants Management Contact(s):

Debbie Stauffer
Division of Grants and Contracts Management
National Institute on Aging
Gateway Building, Room 2N212

7201 Wisconsin Avenue
Bethesda, MD 20892-9205
Telephone: (301) 496-1472
Fax: (301) 402-3672

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals ( as mandated by the Health Research Extension Act of 1985 (, and the USDA Animal Welfare Regulations ( as applicable.

Human Subjects Protection:
Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (“NIH Policy for Data and Safety Monitoring,” NIH Guide for Grants and Contracts,

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible ( Investigators should seek guidance from their institutions, on issues related to institutional policies and local institutional review board (IRB) rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh-Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are: (1) first produced in a project that is supported in whole or in part with Federal funds; and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research” (; a complete copy of the updated Guidelines is available at The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the SF424 (R&R) application; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at

Human Embryonic Stem Cells (hESC):
Criteria for Federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding ( It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators funded by the NIH must submit or have submitted for them to the National Library of Medicine’s PubMed Central (see, an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication. The NIH Public Access Policy is available at ( For more information, see the Public Access webpage at

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (HHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the HHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website ( provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, Internet addresses (URLs) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles. Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at and is not subject to the intergovernmental review requirements of Executive Order 12372. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see:

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