PERIODONTAL DISEASES: MICROBIAL AND HOST GENOMICS/PROTEOMICS

RELEASE DATE:  April 24, 2003
 
RFA:  DE-04-001
 
National Institute of Dental and Craniofacial Research (NIDCR) 
 (http://www.nidr.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER:  93.121

LETTER OF INTENT RECEIPT DATE:  July 29, 2003

APPLICATION RECEIPT DATE:  August 26, 2003
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

The purpose of this RFA is to stimulate research that will employ 
prokaryotic/eukaryotic genomic and proteomic techniques to analyze the 
molecular interactions that occur between oral bacteria and host cells 
(i.e. bacteria-bacteria, bacteria-host cell, and host cell-host cell) 
associated with the pathogenesis of periodontal diseases.   The 
ultimate goal is to use this information to prevent, treat or diagnose 
periodontal diseases.

RESEARCH OBJECTIVES
 
Background

Periodontitis is a chronic inflammatory disease that destroys the 
tissues that surround and support the teeth.  These diseases are 
complex, with genetic, microbial, immunological and environmental 
factors determining disease risk, progression, and course.  Periodontal 
diseases are a significant public health burden in the United States.  
Total expenditure on periodontal and preventive periodontal procedures 
(dental cleaning and oral hygiene instruction) was $14.3 billion in 
1999.  Severe periodontal diseases (having 4mm or more of attachment 
loss) increase in prevalence with age, with approximately 50% of 55-64 
years old having evidence of severe disease.  By age 75, roughly two 
thirds of all adults have severe periodontitis and one third of them 
have 6 mm or more of attachment loss.  Males are more likely than 
females to have at least one tooth with 6 mm or more of attachment 
loss, and severe periodontal diseases are higher in non-Hispanic blacks 
and persons in low socioeconomic groups at each age group.  Early onset 
periodontitis, a severe and rapidly progressive disease occurring in 
individuals under the age of 35, is far more common in African American 
blacks (10.0%), than Hispanics (3.0%) and whites (1.3%).  Some forms of 
periodontal diseases progress very rapidly, destroying the tissues that 
surround and support the teeth.  Risk factors for periodontal diseases 
include smoking, colonization of the subgingival plaque with pathogenic 
bacteria, diabetes, race and age.  Periodontitis has been associated 
with systemic diseases and conditions, such as stroke, atherosclerosis, 
diabetes, respiratory disease, and adverse pregnancy outcomes.  

During the last five years, periodontal research supported by the NIDCR 
has led to significant advances including identification of hundreds of 
species of uncultured bacteria by 16S ribosomal RNA genetic techniques, 
complete or partial sequencing of many periodontopathic bacterial 
strains, a more complete appreciation of the importance and complexity 
of the microbial biofilms, host immune responses involved in chronic 
inflammation, molecular analysis of alveolar bone loss, and the 
biological basis for accelerated tissue regeneration.   Periodontal 
diseases are initiated by a complex network of molecular interactions 
between bacteria growing as a biofilm in the subgingival crevice and 
the host tissues that surround and support the teeth.  The damage to 
host soft and hard tissues appears to be largely the result of multiple 
factors produced during the destructive chronic inflammatory response 
to the bacteria and their products, as well as bacterial proteinases 
and cytotoxins released from subgingival biofilms. 

Genomics refers to the study of the identity of all genes within the 
chromosome of a cell.   Functional genomics research is directed towards 
elucidating the organization of the genes and their expression patterns 
under highly defined conditions.   The human, animal and microbial 
genome sequencing projects are providing a rich genetic resource to 
better understand periodontal diseases.  The development of high 
throughput analyses of genomic data makes it possible to explore 
patterns of gene expression in cells of the periodontium (both 
eukaryotic and prokaryotic), and thus better define the precise 
pathogenesis of diseases.   DNA microarray technologies provide 
investigators with the ability to assess changes in gene expression on a 
genome-wide basis, providing a "global" perspective of how an organism 
responds to a specific stress, drug or toxicant.

Proteomics, the study of the proteome (i.e., the complete set of 
proteins expressed by the genome of an organism, cell or tissue type), 
seeks to unravel the biological complexity encoded by the genome.  
Proteomics builds on and complements the knowledge gained from genomics 
by revealing the levels, activities, regulation and interactions of 
every protein in the cell.  Study of the proteome is more complex than 
that of the genome.  It is estimated that the number of proteins to be 
examined is at least an order of magnitude greater than the number of 
genes, in part because proteins can undergo a variety of post-
translational modifications.  Moreover, the composition of the proteome 
is dynamic and constantly changing in response to the environment and 
there are multiple possible interactions among proteins.  Protein chips 
that can simultaneously identify large numbers of proteins, although 
more difficult to produce and to handle than DNA microarrays, offer 
insight into the patterns of proteins associated with health and 
disease.   High throughput structure determination using x-ray 
crystallography and identification using nuclear magnetic resonance 
spectrometry are providing exciting insight into host and microbial 
proteins under different environmental conditions.  Importantly, the 
data generated by these research projects are becoming more manageable 
through impressive developments in the field of bioinformatics.  

Genomics and proteomics provide a new gateway to understanding the 
etiology and pathogenesis of periodontal diseases.  For example, 
complete transcriptional profiling of microbes isolated directly from 
human subgingival biofilms, can show gene expression patterns required 
for nutrient acquisition, motility and production of virulence factors.  
Recent studies also show that microbial and host proteins are modified 
posttranslationally by cellular proteases, resulting in unexpected 
structure and biological functions.  Such global information about 
genes and proteins provides a rational basis for identification of 
molecular targets that could be used for better diagnoses, prevention, 
or treatment of these diseases.  The identification of single 
nucleotide polymorphisms involved in allelic variants of genes, can 
lead to information on patient-specific genes involved in disease 
pathogenesis.  Genomic and proteomic information can define cellular 
networks of response genes, identify target molecules of toxicity, 
provide future biomarkers, and identify individuals with varied 
susceptibility to infection, inflammation, the environment and/or 
drugs.  The application of these tools to oral health research is 
causing a paradigm shift in the study and understanding of periodontal 
diseases.  Integration of information from the genome sequencing 
projects, comparative and microbial genomics, proteomics, 
bioinformatics, and related technologies will provide the basis for 
proactive approaches for prevention, diagnosis and treatment.

Scope 

The objective of this RFA is to stimulate research to use contemporary 
high-throughput technology to identify and characterize genes 
(genomics) and proteins (proteomics) that are associated with 
periodontal diseases and health.  Findings from these studies will 
establish a scientific basis for identification of logical targets for 
the prevention, diagnosis and treatment of these diseases.  

Examples of responsive projects include, but are not limited to: 

o Studies of the intracellular signaling pathways activated during 
bacteria-host cell interactions;   

o Analysis of all structural proteins involved in microbial attachment 
to host tissue cells; 

o Application of innovative proteomic technologies such as isotope-
coded affinity tag (ICAT) peptide labeling, SELDI-TOF, multi-
dimensional chromatographic technologies (such as coupling LC-LC with 
MS/MS), antibody arrays, protein chips, and yeast two-hybrid or phage-
display assays to study host and microbial proteins involved in 
periodontal diseases;   

o Identification of proteins and other molecules involved in cross talk 
between bacteria and host cells; 

o Studies on total gene expression by bacterial growing in "normal" 
versus "pathogenic" biofilms;  

o Analysis of the gene and protein profiles to establish an objective 
definition of active versus quiescent periodontal disease; 

o Total gene expression in subgingival plaque bacteria exposed to host 
innate and acquired immune factors;

o Gene and protein profiles of host leukocytes recruited to 
gingival/periodontal lesions; 

o Molecular profiles of alveolar bone cells in healthy versus 
chronically inflamed tissues; 

o Microbial gene expression in mixed microbial ecosystems; 

o Contact-induced gene expression in bacteria; 

o Computational models to understand the roles of gene-environment 
interactions in disease;

o Epithelial cell gene expression resulting from interactions with 
microbes and microbial soluble factors; 

o Studies on molecular bacterial physiology using real time 
technologies;

o Studies characterizing protein-protein interactions and their 
consequences on inflammation in the gingiva.  

o Quantitative studies focused on protein modifications that will 
enhance our knowledge of periodontal disease pathogenesis;

o Studies characterizing the molecular mechanisms controlling temporal 
and spatial regulation of protein expression networks in a cell; and,   

o Studies to identify and characterize the relationship between gene 
expression profiling and protein interaction networks for cellular 
processes.
 
Applications that propose only to survey and catalog gene or protein 
expression patterns in response to exposure to environmental conditions 
will be considered non-responsive to this RFA.  Applications should 
focus on enhancing our understanding of the mechanisms and pathways by 
which genes and proteins contribute to the prevention, diagnosis and 
treatment of periodontal diseases.

MECHANISM OF SUPPORT
 
This RFA will use NIH R01 and R21 award mechanisms.  As an applicant 
you will be solely responsible for planning, directing, and executing 
the proposed project.  This RFA is a one-time solicitation.  Future 
unsolicited, competing-continuation applications based on this project 
will compete with all investigator-initiated applications and will be 
reviewed according to the customary peer review procedures.  The 
earliest anticipated award date is April 2004.  Applications that are 
not funded in the competition described in this RFA may be resubmitted 
as NEW investigator-initiated applications using the standard receipt 
dates for NEW applications described in the instructions to the PHS 398 
application.  

This RFA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise 
follow the instructions for non-modular research grant applications.  
This program does not require cost sharing as defined in the current 
NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.  

FUNDS AVAILABLE
 
The NIDCR intends to commit approximately $2.0 million total cost 
(direct cost and applicable facilities and administrative F&A cost) in 
FY2004 or FY2005 to fund six to eight new and/or competitive 
continuation grants in response to this RFA. An R01 applicant may 
request a project period of up to four (4) years and a budget for 
direct costs up to $500,000 per year.  An R21 applicant may request 
direct costs up to $275,000 over a two year period.  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 NIDCR provide 
support for this program, awards pursuant to this RFA are contingent 
upon the availability of funds and the receipt of a sufficient number 
of meritorious applications. At this time, it is not known if this RFA 
will be reissued. 
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
o Faith-based or community-based organizations 

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution 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 programs.   

SPECIAL REQUIREMENTS 
 
Applicants should request funds for one trip per year for an annual 
meeting to be held at NIH in Bethesda, MD.  The purpose for these 
meetings is to discuss scientific advances in the genomics and 
proteomics of periodontal diseases, and to discuss the potential for 
collaborations, data sharing, data repositories and other research 
opportunities.

WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

Dennis F. Mangan, Ph.D.
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN-12J
Bethesda, MD  20892-6402
Telephone:  (301) 594-2421
FAX:  (301) 480-8319
Email:  Dennis.Mangan@nih.gov

o Direct your questions about peer review issues to:

H. George Hausch, Ph.D.
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
Building 45, Room 4AN-44F
Bethesda, MD  20892-6402
Telephone:  (301) 594-2904
FAX:  (301) 480-8303
Email:  George.Hausch@nih.gov

o Direct your questions about financial or grants management matters to:

Mary Daley
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN-55
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
FAX:  (301) 480-8303
Email: md74u@nih.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does 
not enter into the review of a subsequent application, the information 
that it contains allows NIDCR staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning 
of this document.  The letter of intent should be sent to Dr. Hausch at 
the address listed above. 

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.
 
SUPPLEMENTAL INSTRUCTIONS FOR R21 APPLICATIONS: 

All application instructions outlined in the PHS 398 application kit 
are to be followed with the following modifications for R21 
applications:

1. FACE PAGE, Item 6:  Up to a total of two years of support may be 
requested.  Total direct costs for the two years may not exceed 
$275,000.  Normally, no more than $200,000 may be requested in any 
single year.    

2. RESEARCH PLAN:  Items a-d may not exceed fifteen (15) pages, 
including tables and figures.  The following information should be 
taken into account for items a, b and c:  

o  Item a, SPECIFIC AIMS--The instructions for this section suggest 
that the applicant state "the hypotheses to be tested".  Since some 
applications submitted in response to this RFA may also be design- or 
problem-driven (e.g., development of novel technologies), or need-
driven (initial research to develop a body of data upon which future 
research will build), hypothesis testing per se may not be the driving 
force in developing such a proposal and, therefore, may not be 
applicable.  The application should state the hypotheses, design, 
problem and/or need which will drive the proposed research.

o  Item b, BACKGROUND AND SIGNIFICANCE--In this section, it is 
important to identify clearly how the application addresses the 
specific objectives of this RFA and the purpose of the R21 mechanism.

Item c, PRELIMINARY STUDIES/PROGRESS REPORT—No preliminary data are 
required for an R21 application.  

3.  APPENDIX.  Up to five articles may be submitted as appendix 
materials.  

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:   R01 
applications requesting up to $250,000 per year in direct costs and all 
R21 applications must be submitted in a modular grant format.  The 
modular grant format simplifies the preparation of the budget in these 
applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research 
grant application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  Failure to use 
this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed original of the 
application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application 
must be sent to:

H. George Hausch, Ph.D.
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
Building 45, Room 4AN-44F, MSC 6402
Bethesda, MD  20892-6402
 
APPLICATION PROCESSING: Applications must be received by the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review.
 
Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and 
funding assignment within 8 weeks.

The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  However, when a previously unfunded application, 
originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW 
application.  That is the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text 
must not be marked to indicate the changes.  While the investigator may 
still benefit from the previous review, the RFA application is not to 
state explicitly how.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDCR.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further 
consideration.  Applications that are complete and responsive to the 
RFA will be evaluated for scientific and technical merit by an 
appropriate peer review group convened by the NIDCR in accordance with 
the review criteria stated below.  As part of the initial merit review, 
all applications will:

o Receive a written critique
o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications 
under review, will be discussed and assigned a priority score
o Receive a second level review by the NIDCR National Advisory Council. 
 
REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
In the written comments, reviewers will be asked to discuss the 
following aspects of your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your application does not need to 
be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, 
you may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  What will be the effect of these studies on the concepts or 
methods that drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
aims of the project?  Do you acknowledge potential problem areas and 
consider alternative tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project 
challenge existing paradigms or develop new methodologies or 
technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to your 
experience level as the principal investigator and to that of other 
researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your work 
will be done contribute to the probability of success?  Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements?  Is there 
evidence of institutional support?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the 
following items will be considered in the determination of scientific 
merit and the priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of 
human subjects and protections from research risk relating to their 
participation in the proposed research will be assessed. (See criteria 
included in the section on Federal Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy 
of plans to include subjects from both genders, all racial and ethnic 
groups (and subgroups), and children as appropriate for the scientific 
goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the 
sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals 
are to be used in the project, the five items described under Section f 
of the PHS 398 research grant application instructions (rev. 5/2001) 
will be assessed.  

ADDITIONAL CONSIDERATIONS 

o DATA SHARING:  The adequacy of the proposed plan to share data. 

o BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

o R21 APPLICATIONS:  The potential for ground-breaking, precedent-
setting research, with particular emphasis on novel and innovative 
approaches; and the potential to stimulate new concepts or approaches 
regarding important biomedical/behavioral problems, or provide a 
technique/system of wide applicability.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  July 29, 2003  
Application Receipt Date:  August 26, 2003
Peer Review Date:  November 2003
Council Review:  January 20-21, 2004
Earliest Anticipated Start Date:  April 2004

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) 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. 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research 
components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

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 AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at http://
grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.   
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 new 
PHS Form 398; 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.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS:  The NIH maintains a policy that children (i.e., individuals 
under the age of 21) must be included in all human subjects research, 
conducted or supported by the NIH, unless there are scientific and 
ethical reasons not to include them. This policy applies to all initial 
(Type 1) applications submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines" on the inclusion of children as 
participants in research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm

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 proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/
NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC):   Criteria for federal funding of 
research on hESCs can be found at 
http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).   It is the responsibility of the applicant to 
provide 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. 

PUBLIC 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 public 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 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA 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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:   
The Department of Health and Human Services (DHHS) 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 DHHS Office for Civil Rights (OCR). 
Those who must comply with the Privacy Rule (classified under the Rule 
as "covered entities") must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule 
reside with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) 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 http://grants.nih.gov/grants/guide/notice-files/
NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and 
proposals for NIH funding must be self-contained within specified page 
limitations. Unless otherwise specified in an NIH solicitation, Internet 
addresses (URLs) should not be used to provide information necessary to 
the review because reviewers are under no obligation to view the 
Internet sites.   Furthermore, we caution reviewers that their anonymity 
may be compromised when they directly access an Internet site.

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 RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject 
to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  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 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 NIH Grants Policy Statement can be 
found at http://grants.nih.gov/grants/policy/policy.htm.  

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.

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