Bioengineering Research Partnerships
Participating Institutes and Centers (ICs) of the National Institutes of
Health (NIH) invite applications for R01 awards to support Bioengineering Research
Partnerships (BRPs) for basic, applied, and translational multi-disciplinary
research that addresses important biological or medical research problems.
In the context of this program, a partnership is a multi-disciplinary research
team that applies an integrative, systems approach to develop knowledge and/or
methods to prevent, detect, diagnose, or treat disease or to understand health
and behavior. The partnership must include appropriate bioengineering or allied
quantitative sciences in combination with biomedical and/or clinical components.
The Principal Investigator (PI) also serves as the project manager and must
be capable of leading the proposed effort. A BRP may propose design-directed,
developmental, discovery-driven, or hypothesis-driven research at universities,
national laboratories, medical schools, large or small businesses, or other
public and private entities or combinations of these entities. It is expected
that a BRP will have a well-defined goal or deliverable that will be achieved
based on objective milestones specified in the initial application. On 11 October
2001, the NIH issued a related program announcement (PA) PA-02-011 (http://grants.nih.gov/grants/guide/pa-files/PA-02-011.html)
for Bioengineering Research Grants (BRGs). The BRGs differ from the BRPs in
that the research will be performed in a single laboratory, by a single
investigator, or by a small group of investigators. On 16 January 2003, the
NIH issued another related PA (PA-03-058), (http://grants.nih.gov/grants/guide/pa-files/PA-03-058.html)
for Exploratory/Developmental (R21) Bioengineering Research Grants (EBRG).
The EBRGs differ from the BRPs in that (1) the research will be performed in
a single laboratory, by a single investigator, or by a small group of investigators
and (2) the projects are high-risk/high-payoff in nature (R21 mechanism) as
compared to the R01-type grants supported by the BRP program.
Many of today's biomedical problems are best addressed using a multi-disciplinary
approach that extends beyond the traditional biological and clinical sciences.
Bioengineering integrates principles from a diversity of technical and biomedical
fields and crosses the boundaries of many scientific disciplines represented
throughout academia, laboratories, and industry. The creativity of interdisciplinary
teams is resulting in new basic understandings, novel products, and innovative
technologies for addressing biomedical problems. Recognizing the importance
of bioengineering in public health, the Bioengineering Consortium (BECON) was
established in 1997 as a focus for bioengineering activities at the NIH. To
facilitate communication between the allied and biomedical disciplines and
to provide input from the scientific community on research needs and directions,
the BECON has held annual two-day symposia on emerging topics of interest related
to bioengineering including bioengineering (1998), bioimaging (1999), nanotechnology
(2000), reparative medicine (2001), biosensors (2002), and team science (2003).
Summaries of the proceedings and recommendations of these symposia are available
on the internet at http://www.becon.nih.gov/becon_symposia.htm.
Discussions and recommendations of symposia participants aided in the formulation
of the BRP, BRG, and EBRG PAs. It is expected that some applications submitted
in response to the BRP, BRG, and EBRG PAs will focus on technology development
rather than on proving or disproving scientific hypotheses. In support of this
approach, NIH instructions to applicants and review criteria emphasize that
a project may "...test a stated hypothesis, create a novel design, solve a
specific problem, or develop new technology" (PHS 398 instructions for the
research plan).
The primary objective of this PA is to encourage basic, applied, and translational
bioengineering research that could make a significant contribution to improving
human health. Bioengineering integrates physical, engineering, and computational
science principles for the study of biology, medicine, behavior, or health.
It advances fundamental concepts, creates knowledge from the molecular to the
organ systems level, and develops innovative biologicals, materials, processes,
implants, devices, and informatics approaches for the prevention, diagnosis,
and treatment of disease, for patient rehabilitation, and for improving health.
Some BRP projects may propose research that could lead to a novel device as
a product. Partnership with companies that have relevant expertise or that
may eventually be involved in commercialization is appropriate under the BRP
program.
A second objective is to encourage collaborations and partnerships among
the allied quantitative and biomedical disciplines. A BRP must bring together
the necessary physical, engineering, and computational science expertise with
biological or clinical expertise and resources to address a significant area
of bioengineering research within the mission of the NIH. In addition to the
benefits to be derived from the research, the collaborations and partnerships
can create opportunities for trans-disciplinary communication and training
for a new generation of scientists capable of interacting across traditional
technical boundaries. Applications for a BRP award should focus on an area
of basic, applied, translational, behavioral, or clinical research in bioengineering
that supports the missions of the participating NIH institutes and centers
and where progress is likely to make a significant contribution to improving
human health. Some NIH institutes and centers have indicated that they will
only consider BRP applications in specific focus areas. These institutes and
focus areas are available at http://www.becon.nih.gov/becon_brpareas.htm.
This PA uses the NIH R01 award mechanism. As an applicant, you are solely
responsible for planning, directing, and executing the proposed project. This
PA uses just-in-time concepts. It also uses the modular budgeting 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 budget format. Otherwise follow the
instructions for non-modular budget 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.
The initial period of support of a BRP award may be up to five years. The
award may be competitively renewed for a total of up to ten years of NIH funding.
Competing renewal and revised applications for BRP grants are to be received
at the NIH on the same receipt dates as new BRP applications.
For new grants, the maximum total (direct plus facilities and administrative
[F&A] costs) budget to be awarded in any year is $2 million. The number
of awards and level of support will depend on the number of applications of
high scientific merit that are received and the availability of funds. Funding
in subsequent years will be contingent upon satisfactory progress during the
preceding year(s) and the availability of funds. Applicants are strongly encouraged
to discuss budget requests with NIH scientific and financial contacts listed
under WHERE TO SEND INQUIRIES prior to submission. Grantees have the authority
to extend the duration of a BRP grant on a no-cost basis. This extension provides
additional time to use funds that remain available at the end of the project
period to continue pursuing the aims of the grant. Grantees should notify the
Grants Management Officer of the awarding institute or center of the no-cost
extension as early as possible and before the expiration of the grant.
Research Focus Areas: Applicants are strongly advised to contact IC scientific
program staff listed under WHERE TO SEND INQUIRIES to discuss the relevance
of their proposed work to the institute's mission before preparing a detailed
research application. Detailed information on research missions and programs
for each NIH institute and center is available on the participating ICs Web
sites, which are listed at the beginning of this PA. Some NIH institutes and
centers have indicated that they may only want to consider BRP applications
in specific focus areas. As they are available, these institutes and focus
areas will be posted at http://www.becon.nih.gov/becon_brpareas.htm.
Letter of Intent: Prospective applicants are asked to submit a letter of
intent that includes the following information: Number and title of this PA;
Descriptive title of the proposed research; Name, address, telephone number,
and e-mail address of the Principal Investigator; List of participating institutions
and key personnel. 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 NIH staff to estimate the potential review workload,
plan the review, and evaluate programmatic impacts of the proposals. The letter
of intent should be sent to: Dr. Richard E. Swaja, National Institute of Biomedical
Imaging and Bioengineering (NIBIB), 6707 Democracy Boulevard, Suite 200, Bethesda,
MD 20892-5469 USA, 301-451-4779 fax: 301-480-4973, email: swajar@nibib.nih.gov
BRP Organizational Structure, Leadership, and Management: An organizational
structure that clearly defines the partnership and relationships among the
various components must be developed and described in the application. The
BRP size, structure, and mode of operation should match the needs and scope
of the proposed research. NIH policy requires that a single PI be designated
on the face page of all applications. While this individual is responsible
for the scientific and technical aspects, as well as the proper conduct of
the project, the structure of the BRP may involve more than one individual
in developing the application and in making decisions concerning planning,
management, staffing, and resource allocation. In recognition of the essential
intellectual and/or technical contributions of the lead scientists responsible
for developing and implementing the goals of the proposal, the BRP organizational
structure must include a "Leadership Statement" that specifies the roles of
the individuals that provide major intellectual and/or technical contributions.
The PI has the responsibility and authority to use BRP funds in the most productive
way to achieve the goals defined at the time of the award. To accomplish these
tasks, the PI in collaboration with other individuals identified in the "Leadership
Statement" can adjust funding among BRP participants to support new partners
or to reduce support to existing partners as needed. The BRP should establish
a Scientific Steering Group that consists of representatives from each of the
partnering organizations and meets regularly to discuss project status, problems,
and directions. Those individuals identified in the "Leadership Statement," who
together would have the intellectual and leadership responsibilities normally
attributed to the PI, would likely be members of the Scientific Steering Group.
BRP PI Meeting: BRP PIs will meet annually in Bethesda, Maryland, to share
results, to ensure that the NIH has a coherent view of the advances in these
fields, and to have an opportunity for collective problem solving among the
PIs. The cost of participating in this annual meeting should be included in
the BRP budget.
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet
(D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier
when applying for Federal grants or cooperative agreements. The DUNS number
can be obtained by calling 866-705-5711 or through the web site at http://www.dunandbradstreet.com/.
The DUNS number should be entered on line 11 of the face page of the PHS 398
form. The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, 301-435-0714,
e-mail: GrantsInfo@nih.gov.
Application Receipt Dates: New and competing renewal applications submitted
in response to this PA will be accepted on January 21, 2004; August 20, 2004;
January 20, 2005; August 19, 2005; January 20, 2006; and August 22, 2006. These
are the dates that applications must be received at the NIH.
Applications must be received on or before the receipt dates described as
listed on the first page of this PA. The CSR will not accept any application
in response to this PA that is essentially the same as one currently pending
initial review unless the applicant withdraws the pending application. The
CSR will not accept any application that is essentially the same as one already
reviewed. This does not preclude the submission of a substantial revision of
an unfunded version of an application already reviewed, but such application
must include an Introduction addressing the previous critique.
Contact: Dr. Richard E. Swaja, NIBIB, 6707 Democracy Boulevard, Suite 200,
Bethesda, MD 20892-5469 USA, 301-451-4779, fax: 301-480-4973, e-mail: swajar@nibib.nih.gov;
Dr. Eileen Bradley, Center for Scientific Review, NIH, 6701 Rockledge Drive,
Bethesda, MD 20892-0001, 301-435-1179, fax: 301-480-2241, e-mail: bradleye@csr.nih.gov
Circulating Cells in Cancer Detection
The purpose of this PA is to develop novel technologies for capturing, enriching,
and preserving exfoliated abnormal cells and macromolecules in body fluids
or effusions and to develop methods for concentrating the enriched cells for
biomarker studies. In the context of this PA, we have extended the definition
of exfoliation to include not only the cellular materials, but also subcellular
materials, such as DNA and proteins. In body fluids, such as sputum, the number
of exfoliated tumor cells is often small compared to the number of non-neoplastic
cells. Therefore, the detection of exfoliated abnormal cells by routine cytopathology
is often limited because few atypical cells may be present in the specimen.
There may be difficulty in separating dysplastic cells from non-specific reactive
changes and degenerating cells or variation in diagnostic criteria. Furthermore,
exfoliated cells are frequently contaminated with normal cells, bacteria, and
other cellular debris, which makes molecular analysis difficult without physical
separation of the neoplastic cells. Thus, the development of enrichment methods
becomes prerequisite for the routine detection of small numbers of exfoliated
cells and small amounts of subcellular materials in biological fluids for molecular
analysis. Similarly, subcellular materials are in amounts that may not be detectable
by available technologies and therefore the enrichment of such materials is
of paramount importance. Enrichment will allow exfoliated cells and subcellular
molecules, for example from urine, to be used for genomic, proteomic, and epigenomic
analyses that may lead to improvements in the detection of bladder cancer through
measurements of alterations in expressed genes, peptide profiles, and epigenetic
markers.
The most common human tumors arise from epithelial surfaces (e.g. colon,
lung, prostate, oral cavity, esophagus, stomach, uterine cervix, bladder).
Their development often becomes apparent when tumor cells exfoliate spontaneously
into sputum, urine, or even into various effusions. The molecular and genetic
abnormalities within these exfoliated cells could be used to detect and identify
precancerous lesions or very early stage cancer if highly sensitive technologies
were clinically available to identify the few abnormal cells among millions
of normal cells. For example, detection of widespread microsatellite instability
(MSI), as demonstrated by expansion or deletion of repeat elements of DNA,
may be adapted for exfoliated cells in general. With the advent of PCR-based
detection of DNA from rare neoplastic cells in body fluids, mutations have
been detected in ras genes from the stools of patients with colorectal cancer,
in p53 from the urine of patients with bladder cancer, and in p53 genes in
the sputum of patients with lung cancer. As these assays are complex and technically
challenging, they depend on the development of novel technologies for isolating
and enriching cells or subcellular materials of interest. Abnormal exfoliated
cells can be routinely identified by cytologic examination of brushings and
fluids, for instance, from bronchi, pancreatic ducts, voided urine, and effusions.
Currently, fluids are usually processed by centrifugation or membrane filtration.
However, the detection of abnormal exfoliated cells, for instance, cancer cells
by routine cytopathological examination may be limited because the number of
abnormal cells may be very small compared to the number of normal cells, is
difficult. Alternatively, the cellular and nuclear changes in abnormal cells
may be minimal compared to normal cells. This is particularly true of cytological
examinations of urine cytology, where many low-grade papillary lesions are
often missed. New PCR-based technologies may substantially enhance the sensitivity,
but current technologies for isolating and analyzing exfoliated cells are too
cumbersome to be of practical utility. The cellular and molecular changes that
ensue during tumor progression do so over a number of years and in an apparently
stochastic manner. This progressive accumulation of genetic and epigenetic
changes in precancerous cell populations eventually confers the malignant phenotype
on emerging clonal subpopulations. In human and animal clinical and experimental
models, the progression of precancer to cancer is known to be lengthy. For
example, it takes an average of estimated 15 to 20 years for a small adenomatous
polyp to become malignant. Prior to the appearance of a morphologically identified
precancerous lesion, numerous genetic and molecular alterations would have
already occurred. During histological progression into a morphologically identifiable
lesion, the stochastic process of molecular events in different cells confers
genetic heterogeneity.
Finding molecular and genetic biomarkers of malignancy is particularly important
in detecting the emergence of precancerous cell populations and is what the
NCI considers to be an "Extraordinary Opportunity." In these earliest stages
of neoplasia, lesions should be amenable to complete eradication. This principle
has been well-demonstrated in cervical neoplasia, where screening for dysplastic
exfoliated cells can result in a 70% or greater reduction in the cervical cancer
mortality. During the early stages of cancer development, there is a window
of opportunity to detect precancerous cells with genetic or molecular biomarkers
that identify and characterize their progression towards cancer. Detection
of genetic abnormalities in preneoplastic lesions poses challenges because
of the small size of lesions, the heterogeneity of precancerous cells, and
their dilution by normal cellular constituents. Therefore, assays should be
tailored to detect a small number of abnormal cells or molecules among a large
number of normal cells or molecules in biological fluids, such as in colonic
washes of the gastrointestinal tract, in sputa, and in bronchial biopsies.
In order to detect and analyze precancerous and cancerous cells in biologic
fluids, there are a variety of approaches. The most appropriate approach depends
upon 1) the type of biological fluid (sputum, bronchial washing, cervical brushing,
voided urine, etc.), and 2) the form of analysis to be performed (e.g., cytopathological
analysis, morphometric analysis, molecular biomarkers for specific receptors
or genetic changes, FISH-or-PCR based analyses). All of these approaches require
an enrichment of atypical epithelial cells through selective processing to
concentrate the assay target of interest. The enrichment methods currently
used can be grouped into the following two broad categories: 1) mechanical
(centrifugation, cytospin, sucrose gradients, etc.) and 2) antibody-based selection
with mechanical separation (FACS - flow assisted cell sorting, MACS - magnetic
assisted cell sorting, etc.). While one type of enrichment process can be sequentially
added to another to improve the yield, all of these methods have good but not
adequate sensitivity or specificity required for detecting precancerous cells
in body fluids. Given that the concentration of these cells or molecules can
be very low compared to other commonly present cell types or molecules, one
needs enrichment factors of 1 to 10,000 or 1 to million.
More than 80 percent of human tumors originate from epithelial cells, often
at a mucosal surface, and are clonal in origin. Precancerous exfoliated cells
can be routinely identified in pathology departments by cytologic examination
of washings or brushings from bronchi, oral cavity, esophagus, stomach, bile
and pancreatic ducts, sputum and urine; however, the detection of exfoliated
cancer cells by routine cytopathological examination is limited because of
the presence of few atypical cells in specimens, the difficulty of distinguishing
low grade dysplasias from non-specific reactive or inflammatory changes, and
the low sensitivity and specificity of the available diagnostic methodology.
These limitations are particularly true of urine cytology, where most low-grade
papillary lesions are missed on cytologic examination of urine. New PCR-based
technologies may substantially enhance sensitivity, but current technologies
for isolating exfoliated cells are too cumbersome to be of practical utility.
For example, exfoliated cells are frequently contaminated with normal cells,
bacteria, and other cellular debris, making molecular analysis difficult without
further physical separation of neoplastic cells. Therefore, the development
of novel, high-throughput, sensitive technologies for sample preparation is
a prerequisite for the successful detection of small numbers of exfoliated
cells or small amounts of subcellular materials, such as DNA and proteins.
There are occasions in which the only biologic materials available from patients
are stored plasma or serum samples. The amount of DNA in these samples are
generally very low when they are obtained from normal (healthy) individuals,
but increased amounts of circulating DNA have been found in cancer. The circulating
DNA in plasma/serum of cancer patients has been shown to reflect the characteristics
of the tumor DNA including molecular changes, such as methylation, point mutations,
and microsatellite instability. Fragmented nucleosomal DNA in plasma resulting
from apoptotic death of the tumor cells may also provide an indication for
tumor DNA. There is a need to develop high-yield technologies to isolate circulating
DNA that can be used for early detection of cancer and the follow-up of the
disease.
The primary purpose of this initiative is to encourage the development of
high-throughput technologies to facilitate the isolation and enrichment of
exfoliated cells and subcellular materials. In pursuit of these goals, the
NCI invites applications that address the following areas: 1) Development of
high-throughput technologies for identifying abnormal exfoliated cells and
subcellular materials in body fluids; 2) Development of sampling technologies
for capturing and preserving exfoliated tumor cells and subcellular materials
in body fluids; 3) Development of enrichment methods for the isolation of tumor
cells and subcellular materials; 4) Development of sensitive, high-throughput
molecular, cytomorphometric, immunologic, and other relevant technologies to
isolate tumor cells or subcellular materials in malignant effusions to help
detect low tumor burden and distinguish reactive cells from tumor cells.The
long-term goal, to which this initiative will eventually lead, is the development
of panels of well-characterized biomarkers derived from exfoliated cells that
can be sampled in the clinical setting. These methodologies will be tested
and validated in future population-based clinical trials, and integrated into
a comprehensive information system that will be developed under the Early Detection
Research Network.
This PA will use the NIH exploratory/developmental (R21) award mechanism.
As an applicant, you will be solely responsible for planning, directing, and
executing the proposed project. The applicant may request a project period
of up to two years with a combined budget for direct costs of up $275,000 for
the two year period. For example, the applicant may request $100,000 in the
first year and $175,000 in the second year. The request should be tailored
to the needs of the project. Normally, no more than $200,000 may be requested
in any single year. These grants are non-renewable and continuation of projects
developed under this PA will be through the traditional unsolicited investigator
initiated grant program. This PA uses just-in-time concepts. It also uses the
modular budgeting format. (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. 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.
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet
(D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier
when applying for Federal grants or cooperative agreements. The DUNS number
can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/.
The DUNS number should be entered on line 11 of the face page of the PHS 398
form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, 301-435-0714,
e-mail: GrantsInfo@nih.gov.
The title and number of the PA must be typed on line 2 of the face page of
the application form and the YES box must be checked.
Supplementary Instructions: All instructions for the PHS 398 (rev. 5/2001)
must be followed, with these exceptions: Research Plan: Items a - d of the
Research Plan (Specific Aims, Background and Significance, Preliminary Studies,
and Research Design and Methods) may not exceed a total of 15 pages. No preliminary
data is required but may be included if it is available. Please note that a
Progress Report is not needed; competing continuation applications for an exploratory/developmental
grant will not be accepted. Appendix: Use the instructions for the appendix
detailed in the PHS 398 except that no more than 5 manuscripts, previously
accepted for publication, may be included. For the NIH Exploratory/Developmental
Grant (R21), applicants may request direct costs in $25,000 modules, up to
a total direct cost of $275,000 for the combined two year award period.
Applications must be received by or mailed on or before the receipt dates
described at http://grants.nih.gov/grants/funding/submissionschedule.htm.
The CSR will not accept any application in response to this PA that is essentially
the same as one currently pending initial review unless the applicant withdraws
the pending application. The CSR will not accept any application that is essentially
the same as one already reviewed under this PA. This does not preclude the
submission of a substantial revision of an unfunded version of an application
already reviewed, but such application must include an introduction addressing
the previous critique. Unfunded applications previously reviewed as investigator-initiated
applications under a different research grant mechanism may be resubmitted
as a new application under this PA (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-019.html ).
Contact: Mukesh Verma, Division of Cancer Prevention, NCI, Executive Plaza
North, EPN 3144, Bethesda, MD 20892-0001 USA, Rockville, MD 20852 (for express/courier
service), 301-496-3893, fax: 301-402-8990, e-mail: mv66j@nih.gov; Sudhir Srivastava,
Division of Cancer Prevention, NCI, Executive Plaza North, EPN 3142, Bethesda,
MD 20892-0001 USA, Rockville, MD 20852 (for express/courier service), 301-496-3983,
fax: 301-402-8990, e-mail: ss1a@nih.gov
Developmental Mechanisms of Human Structural Birth Defects
The purpose of this PA is to support new, innovative, multidisciplinary,
interactive, and synergistic program projects that integrate basic, translational,
and clinical approaches to understanding the developmental biology and genetic
basis of congenital human malformations. Each program must consist of at least
three component projects. At least one project must be clinical or translational
in nature. The component projects must share a common central theme, focus,
or objective on a specific developmental defect or malformation that is genotypically,
mechanistically, biologically, or phenotypically analogous or homologous in
both animal models and humans. Any non-mammalian or mammalian animal model
may be used, as long as it contributes to the common overall theme or objective
of the program project. If the component projects do not share a common developmental
gene, process, mechanism, pathway, or phenotype, the application will be considered
nonresponsive to this.
Annually, about four percent of all live births in the United States involve
babies with significant structural birth defects (more than 150,000 babies).
Next to accidents, birth defects are the leading cause of death in children;
they account for half of all pediatric hospitalizations. In terms of the economic
costs, billions of dollars are spent over the lifetimes of children born with
any of 17 major, severe, nonfatal birth defects. In sum, structural birth defects
have a great impact on public health, socioeconomics, and family life. A high
priority goal of NICHD's strategic plan is to address the problem of human
structural birth defects. The clinical and epidemiological aspects of human
malformations were addressed at a workshop in 1997. As a result of that workshop,
the National Institute of Child Health and Development (NICHD), the National
Institute of Environmenal Health Sciences (NIEHS), the National Institute of
Dental and Craniofacial Research (NIDCR), and the U.S. Environmental Protection
Agency (U.S. EPA) issued RFA HD-99-002, "Genetic Susceptibility and Variability
of Human Malformations." That initiative funded several R01s and established
a basis for a network of investigators focused on the use of molecular genetic
approaches to the study of genetic susceptibility and epidemiology of human
malformations.
A second workshop was held in 1998 and its recommendations served as the
basis for RFA HD-99-008, "Developmental Mechanisms of Human Malformations",
from which NICHD and NIEHS funded several P01s. An important feature of those
P01s was the emphasis on integrating basic, translational, and clinical research.
Combined with the R01s funded under the first initiative, these projects expanded
the network of researchers focused on the study of structural birth defects.
By issuing this PA, "Developmental Mechanisms of Human Structural Birth Defects," the
NICHD plans to increase the number of basic scientists and clinicians involved
in this network. Now that the sequencing of the human genome is complete, it
is time to capitalize on the rapid advances being made in functional genomics
and proteomics. Broadening the base of PIs involved in this research effort
will promote the translation of these advances from the bench to the bedside.
The purpose of this PA is to support new, innovative, multidisciplinary,
interactive and synergistic program projects that integrate basic, translational,
and clinical approaches to understand the developmental biology and genetic
basis congenital human malformations. Of particular interest to the NICHD are
applications proposing to study embryonic developmental defects of generalized
body patterning and localized anomalies of the skeletal, nervous, and visceral
systems that lead to clinically significant congenital structural malformations.
While applications focusing on developmental disorders that result in mental
retardation and related neurobehavioral disabilities are of interest to the
NICHD, they are outside the scope of this PA. The basic science component projects
may include studies to: 1) identify and characterize the genes, gene products,
mutations, polymorphisms, multigene and gene/environment interactions that
play a role in normal and abnormal embryonic patterning and organogenesis;
2) elucidate the developmental biological processes and pathways, the biochemical,
cellular, molecular, genetic mechanisms, and spatial and temporal gene expression
patterns which are involved in dysmorphogenesis; and 3) examine how teratogens
and nutritional deficiencies disrupt or modify gene expression and basic developmental
processes.
The translational/clinical component projects may include studies to: 1)
characterize and classify genotypes and phenotypes of human malformations that
are comparable in the animal models being examined; 2) develop physical, genetic,
and comparative maps for genes involved in human malformations; 3) identify
the developmental genetic processes and molecular pathogenesis of human malformations
utilizing animal models; and 4) develop innovative molecular genetic methods,
technologies, and strategies to enhance the diagnosis and methods for intervention
of the human malformations.
Applicants are encouraged to incorporate the recent scientific advances in
developmental biology and genetics in their projects and to utilize the many
research resources, bioinformatic databases, and biotechnological tools in
their research cores. The research cores should be structured to share work
effort and research resources (e.g., biotechnology, high-throughput instrumentation,
microarrays, oligonucleotide chips, animal model development, and technical
assistance) among the research projects. The aim of the core is to enhance
the progress, productivity, cost-effectiveness, and outcome of the research
projects.
Applications may include new and innovative approaches to investigate: 1)
genetic defects, nutritional deficiencies, teratogens that perturb, modify,
or alter gene expression during early development; 2) the identity and function
of transcription and growth factors in normal and abnormal gastrulation, embryogenesis,
organogenesis, and patterning, as well as their modification by environmental
agents; and 3) defective embryonic developmental processes and pathways that
ultimately lead to malformations.
Research projects responsive to this PA include, but are not limited to,
the following: 1) Investigations on the identity, characteristics, and mechanisms
of growth factors and growth factor receptors that function in embryonic development
and dysmorphogenesis of the skeletal, nervous, and visceral systems; 2) Studies
of transcription factors regulating gene expression and temporal and spatial
expression patterns during normal and abnormal embryonic development; 3) Studies
of developmental genes, gene products, transcription factors, and growth factors
that function and interact to regulate cell proliferation, cell differentiation,
apoptosis, cell migration, and cell fate in embryonic development; 4) Examination
of genes and molecular mechanisms and interactions that control normal and
abnormal body axes and symmetry during development; 5) Studies to identify,
map, and characterize genes that play a role in signal transduction and biochemical
pathways, cell fate determination, gastrulation, embryogenesis, organogenesis,
body patterning, and how developmental defects, mutations, or susceptible polymorphisms
lead to malformations; 6) Investigations of pharmaceutical, nutritional, and
teratogenic agents and factors that alter genes and developmental processes
and pathways that result in dysmorphologies; 7) Investigations to characterize
and classify genotype/phenotypes of hereditary human malformations and correlate
them to homologs in animal models; 8) Efforts to define pleiotropic effects
that genes and their modifiers have in the spatial and temporal development
of embryonic and/or fetal anomalies; 9) Development and validation of new and/or
improved animal models to study the genes, mutations, mechanisms, and developmental
processes and pathways that cause human malformations; 10) Imaging and gene
expression studies to investigate and monitor the developmental pathogenesis
of dysmorphic features; 11) Investigations of the role of imprinting and epigenetic
factors in the development of major congenital malformations; 12) Studies on
nutritional factors (e.g., folic acid deficiency) and teratogens (e.g., retinoids
and valproic acid) affecting gene/gene, gene/receptor, gene/modifier, and gene/teratogen
interactions that lead to neural tube or other structural defects; 13) Examination
of the role and developmental biology of neural crest cells in normal embryonic
development and how defects in cell proliferation, differentiation, migration,
and patterning may result in major structural birth defects; 14) Elucidation
of the underlying genetic and molecular mechanisms that alter normal developmental
processes in drug-induced (e.g., Accutane, Thalidomide) malformations; 15)
Identification and characterization of polymorphisms/mutations of metabolic
genes that function in the development of structural birth defects. The topics
listed above are only examples, are not in priority order, and are not intended
to be all-inclusive. Investigators are encouraged to explore and develop new,
innovative projects and research cores that are consistent with the overall
objectives of this PA.
Applicants are encouraged to incorporate the recent scientific advances in
developmental biology and genetics in their projects and to utilize the many
research resources, bioinformatic databases, and biotechnological tools in
their research cores. The research cores should be structured to share work
effort and research resources (e.g., biotechnology, high-throughput instrumentation,
microarrays, oligonucleotide chips, animal model development, and technical
assistance) among the research projects. The aim of the cores is to enhance
the progress, productivity, cost-effectiveness, and outcome of the research
projects.
This PA will use the NIH Program Project Grant (P01) award mechanism. The
P01 supports broadly based multidisciplinary research programs that have a
well-defined central research focus or objective. An important feature is that
the interrelationships among the individual projects will result in a greater
contribution to the overall program goals than if each project were pursued
independently. The P01 grant requires a minimum of three interrelated individual
research projects that contribute to the overall program objective. At least
one component project must be translational or clinical in nature. The application
may request support for certain common core resources. As an applicant you
will be solely responsible for planning, directing, and executing the proposed
project. Guidelines for the NICHD Program Project (P01) Grant may be found
at http://www.nichd.nih.gov/funding/dsr_p01_guide.htm.
The Program Director for the overall grant and the principal investigator
for each component project should plan to attend an annual NIH-sponsored two-day
meeting in Bethesda, MD. In addition, this meeting will be attended by investigators
supported through the two previous RFAs (HD-99-002, Genetic Susceptibility & Variability
of Human Malformations, and HD-99-008, Developmental Mechanisms of Human Malformations).
The meeting will provide an opportunity for all the investigators to communicate,
discuss the progress of their research, exchange ideas and information, share
resources, and foster collaborations that are relevant to the research goals
of the NICHD birth defects initiative. This requirement is designed to establish
an interactive network of investigators who are interested in multidisciplinary
approaches to enhancing our understanding of the epidemiology, etiology, pathogenesis,
and developmental biology and genetics of structural birth defects.
All applications should include a request for funds to support attendance
of the Program Director and project principal investigators at the annual meetings,
as well as a statement of agreement to participate in these meetings and to
cooperate with investigators at other program project sites. A data-sharing
plan must be included as outlined in the recent NIH Guide notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet
(D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier
when applying for Federal grants or cooperative agreements. The DUNS number
can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/.
The DUNS number should be entered on line 11 of the face page of the PHS 398
form. The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, 301-435-0714,
e-mail: GrantsInfo@nih.gov.
The title and number of this PA must be typed on line 2 of the face page
of the application form and the YES box must be checked.
Applications submitted in response to this PA will be accepted at the standard
application deadlines, which are available at http://grants.nih.gov/grants/dates.htm.
Application deadlines are also indicated in the PHS 398 application kit.
Applications must be mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm.
The CSR will not accept any application in response to this PA that is essentially
the same as one currently pending initial review unless the applicant withdraws
the pending application. The CSR will not accept any application that is essentially
the same as one already reviewed. This does not preclude the submission of
a substantial revision of an application already reviewed, but such application
must include an Introduction addressing the previous critique.
Contact: Lorette Javois, Developmental Biology, Genetics and Teratology Branch,
Center for Developmental Biology and Perinatal Medicine, NICHD, 6100 Executive
Blvd, 4B01 MSC 7510, Bethesda, MD 20892-7510 USA, 301- 496-5541, fax: 301-480-0303,
e-mail: javoisl@mail.nih.gov