Release Date:  November 29, 2001

RFA:  RFA-ES-02-004

National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  February 1, 2002
Application Receipt Date:       February 19, 2002



The mission of the National Institute of Environmental Health Sciences (NIEHS) 
is to promote research that will ultimately reduce the burden of human illness 
and dysfunction from environmental causes.  Understanding the consequences of 
interactions between environmental factors, individual susceptibility and age 
as it relates to human health and human disease is integral to achieving the 
Institute's mission. Integrated, multi-faceted programs such as the 
Environmental Genome Project (examines how genetic polymorphisms influence 
susceptibility or resistance to environmental exposure) and the National 
Center for Toxicogenomics (combines genetics, genome-wide mRNA expression, 
cell and tissue-wide protein expression, and bioinformatics to understand the 
roles of gene-environment interactions in disease) provide comprehensive 
scientific approaches to unravel the complex relationships between genes, gene 
products and cellular and biological function. To date, a major emphasis has 
been on understanding the organization of the genome and on gene expression 

The purpose of this RFA is to begin to address the biological complexity 
encoded by the genome by focusing on the protein products.  Applications are 
being sought that propose to apply or develop proteomic technologies to 
elucidate the organization and dynamics of metabolic, signaling and regulatory 
networks important to understanding how dysregulation of these pathways may 
lead to human disease as a consequence of environmental exposure.


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 Request for Applications (RFA), 
"Functional Proteomics:  Applications to Environmental Health Research", is 
related to one or more of the priority areas.  Potential applicants may obtain 
a copy of "Healthy People 2010" at


Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 


This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) and the NIH Exploratory/Developmental (R21) award mechanisms.  The 
R01 grant mechanism supports a discrete, specified, circumscribed research 
project that is well-grounded on current knowledge and is to performed by the 
named investigator(s) in an area of research representing his/her/their 
specific interest and competencies.  The R21 grant award mechanism supports 
innovative, high-risk/high-impact research requiring preliminary testing or 
development; exploration of the use of approaches and concepts new to a 
particular substantive area; research and development of new technologies, 
techniques or methods; or initial research and development of data upon which 
significant future research may be built.  Applications will be considered 
high-impact if they demonstrate the potential for groundbreaking, precedent 
setting significance, and high-risk because they either lack sufficient 
preliminary data to ensure their feasibility, or involve using a new model 
system or technique. 

Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  This RFA is a one-time 
solicitation.  Future unsolicited competing continuation applications will 
compete with all investigator-initiated applications and be reviewed according 
to the customary peer review procedures.  The anticipated award date is 
September 2002.


The NIEHS intends to commit approximately $3.5 million in FY 2002 to fund six 
to ten new grants in response to this RFA.  For R21's, an applicant may 
request a project period of two years maximum and a budget for direct costs of 
up to $150,000 per year (six $25,000 modules).  For R01's, an applicant may 
request a project period of up to five years and for applications requesting 
up to $250,000 in direct costs per year, the application must be submitted in 
the modular grant format.  R01 applications requesting budgets greater than 
$250,000 in direct costs must submit detailed budget information with the 
application.  Because the nature and scope of research proposed might vary, it 
is anticipated that the size of each award will also vary.  If the proposed 
budget is to exceed $500,000 in direct costs in any one year, notification and 
discussion with program staff is required at least six weeks prior to 
submission.  Although the financial plans of the NIEHS 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.



The astounding progress made in the science of genomics has had a major impact 
on the practice of biomedical research.  The Human Genome Project and other 
genome sequencing projects have accelerated scientific progress that will have 
important consequences for environmental health research.  High-throughput 
sequencing has made it possible for the discovery of single nucleotide 
polymorphisms at a genome-wide level providing new opportunities to identify 
allelic variants of environmental disease susceptibility genes in the U.S. 
population.  The advent of cDNA microarray technologies has provided to the 
research community the ability to assess changes in gene expression on a 
genome-wide basis, providing a "global" perspective about how an organism 
responds to a specific stress, drug or toxicant.  This information can define 
cellular networks of response genes, identify target molecules of toxicity 
provide future biomarkers, and identify individuals with varied susceptibility 
to environmental agents and/or drugs.  The application of these tools to 
environmental health research has provided a paradigm shift in how gene-
environment interactions in disease are studied. 

Recent programs developed by NIEHS to capitalize on the knowledge gained 
through these sequencing efforts are focusing on functional genomics, that is, 
the functional analysis of genes and their products.  The Environmental Genome 
Project (EGP, and the National 
Center for Toxicogenomics (NCT, are 
examples of comprehensive research programs initiated by NIEHS that have 
applied molecular genetic technologies resulting from the national genome 
efforts to address critical issues in environmental health research.  The 
goals of the EGP are to facilitate the identification of functionally 
important polymorphisms in environmental responsive genes and to facilitate 
epidemiological studies of gene-environment interactions in disease etiology.  
Initially, EGP has focused on systematically identifying and reporting 
polymorphisms in select target genes that may confer altered sensitivity or 
resistance to specific exposures through large-scale re-sequencing efforts. 

Complementary to the EGP is the toxicogenomics effort being launched by NIEHS 
through the National Center for Toxicogenomics (NCT).  Toxicogenomics is a new 
scientific field that elucidates how the entire genome is involved in 
biological responses of organisms exposed to environmental toxicants/ 
stressors.  It combines information from studies of genomic-scale mRNA 
profiling, cell-wide or tissue-wide protein profiling (proteomics), genetic 
susceptibility, and computational models to understand the roles of gene-
environment interactions in disease. 

These functional genomic-based programs have a major emphasis on understanding 
the organization of the genome and on gene expression patterns.  Although the 
information gained from these enterprises will provide a greater insight into 
cellular function that is not possible by studying a few genes at a time, it 
only provides part of the picture.  Proteomics, the study of the proteome 
(i.e., the complete set of proteins expressed by the genome of an organism, 
cell or tissue type during its lifetime) 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 and how these quantities or 
interactions respond to a stimulus. Studying the proteome is complex compared 
to studying the genome.  It is estimated that the number of proteins to be 
studied is at least an order of magnitude greater than the number of genes.  
Proteins can undergo a variety of post-translational modifications.  Moreover, 
the composition of the proteome is dynamic and constantly changing in response 
to its environment and there are many more possible interactions among 

Proteomics goes beyond cataloging the proteins that cells express in health 
and disease states. The importance of proteome research for environmental 
health sciences lies in coupling protein expression profiles with elucidating 
the organization and dynamics of the metabolic, signaling and regulatory 
networks through which the life of the cell is dependent.  This will lead to a 
better understanding of how these networks can become dysfunctional following 
chemical exposures and disease progression and lead ultimately to predicting 
how their function may be manipulated through drug or genetic interventions.  

Research Objectives

One of the goals of this solicitation is to encourage the use or development 
of innovative proteomic technologies to study environmentally responsive 
protein networks.  The technologies exist to observe quantitative changes in 
the expression level of thousands of mRNA transcripts as a consequence of 
exposure to environmental stimuli but the relationship between these changes 
and protein abundance levels is unclear.  A second goal of this RFA is to 
begin to address the dynamics of protein networks within the cell by 
encouraging hypothesis-driven studies that focus on understanding the 
expression, modifications and interactions of proteins on a global scale and 
to provide the bioinformatic tools to analyze this data.  

The integration of this knowledge with gene expression and DNA sequence data 
will provide a holistic view of the dynamics of the cell in response to 
environmental stressors.  Important in this integration is the bioinformatics 
needed to analyze and integrate the large data sets that will be generated. 
Understanding these relationships and how dysregulation of important pathways 
may lead to human disease as a consequence of environmental exposure will 
provide the potential to develop diagnostic and therapeutic approaches to 
mitigate environmentally related diseases. 

Through the NCT and the EGP programs at NIEHS, five of nine categories of 
environmentally responsive genes have initially been identified for in-depth 
study.  These gene categories include DNA repair, cell cycle control, drug 
metabolizing, signal transduction, and apoptosis/cell differentiation.  It is 
suggested that applicants consider these categories for proteomic studies.  
However, applicants are not limited to these examples.  Hypothesis-driven 
proteomic research that is complementary to or derived from an ongoing 
genomics investigation (e.g., gene expression studies or SNP discovery) may be 
proposed.  This RFA will support that part of the research that is focused on 
proteomics.  In vivo and in vitro experimental models are appropriate and can 
include whole animal, organ or tissue cultures, mammalian cell lines, or other 
model systems such as yeast, Drosophilia, and Xenopus.  NIEHS is encouraging 
the 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 address 
their research questions.  In addition, R01 applications submitted in response 
to this RFA must include a discussion of the applicants' bioinformatics 
capacity to support the proposed research.  Personnel for this purpose may be 
included in the budget.  (Note: A bioinformatics component does not need to be 
included for R21s).  Applications that propose only to survey and catalog 
protein expression patterns in response to exposure to environmental agents 
will be considered non-responsive to this RFA.  Applications should focus on 
enhancing our understanding of a particular environmentally responsive pathway 
or interactions among pathways.

Examples of proteomic research topics that may be proposed include, but are 
not limited to the following (not in order of priority):

o Studies characterizing protein-protein interactions to understand how 
stressors may modify binding partners.  This could include global analysis of 
protein modifications resulting from endogenous (e.g., phosphorylation, 
glycosylation) or exogenous (chemical modification) sources and its affect on 
protein expression and cell function. 

o Quantitative studies focused on protein modifications that will enhance our 
knowledge of environmentally related diseases.

o Studies that use proteomic approaches to understand the effects of 
environmental stressors (e.g., chemicals, physical agents, and physiological 
stresses) on the expression and cross talk of metabolic, signaling, DNA 
repair, cell cycle control and apoptosis/differentiation pathways.

o Studies characterizing the molecular mechanisms controlling temporal and 
spatial regulation of protein expression networks in a cell (including within 
or between organelles such as the nucleus, mitochondria, endoplasmic 
reticulum, etc.) or tissue-specific manner at different stages of development, 
differentiation, cell cycle or disease progression.  
o Functional studies using protein chip arrays or other related methods to 
assess protein expression patterns in conjunction with biochemical functions 
of protein classes at the organ/tissue/cell level that may be relevant to 
environmental related disease or dysfunction (e.g., immune function, 
neurological function, reproductive function, hematological, etc.).   

o Studies to identify and characterize the relationship between gene 
expression profiling and protein interaction networks for cellular processes 
as it relates to potential environmentally related disease or dysfunction.

o Studies to develop new proteomic technologies 


Applicants should request funds for one trip/year for an annual meeting of
grantees to be held at NIEHS in Research Triangle Park, North Carolina.  The 
purpose for these meetings is to discuss scientific advances and to discuss 
the potential for collaborations, data sharing, data repositories and other 
research opportunities.

Applicants submitting R01s are expected to discuss in their applications the 
bioinformatics support and methods to be used to analyze the research being 

The policy of the PHS is to make available to the public results and 
accomplishments of activities that it funds.  All awardees must adhere to PHS 
policy for distribution of unique research resources produced with PHS 
funding, which was published at:  
Public databases are being developed at NIEHS for the submission of genomics 
data.  Applicants may be requested to submit findings to these databases. 


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 (
files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 
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 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 


It is the policy of NIH 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 was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 


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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


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:  
Applicants may wish to place data collected under this RFA 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.


Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of the RFA in 
response to which the application may be submitted.  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 IC staff to 
estimate the potential review workload and plan the review.

The letter of intent is to be sent by the letter of intent receipt data to Dr. 
Linda Bass at the address listed below:

Linda Bass, Ph.D.
Scientific Review Administrator
Scientific Review Branch
Office of Program Operations
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-30
79 TW Alexander Drive, Building 4401
Research Triangle Park, NC  27709
Phone:  (919) 541-1307
Fax:  (919) 541-2503


The PHS 398 research grant application instructions and forms (rev. 5/2001) at must be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable format.  For further assistance contact GrantsInfo, 
Telephone 301/710-0267, Email:


The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and NIH staff.  
The research grant application form PHS 398 (rev. 5/2001) at is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.  

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:

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

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:

Linda Bass, Ph.D.
Scientific Review Administrator
Scientific Review Branch
Office of Program Operations
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-30
79 TW Alexander Drive, Building 4401
Research Triangle Park, NC  27709
Phone: (919) 541-1307
Fax:  (919) 541-2503

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.

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.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an Introduction addressing the previous critique.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIEHS.  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 NIEHS in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will receive a written critique and 
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, assigned a priority score, and receive a second level 
review by the National Advisory Environmental Health Sciences 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 the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered in assigning the overall score, 
weighting them as appropriate for each application.  Note that the 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, an 
investigator 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 this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
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?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?  For R01 applications, are the bioinformatic approaches 
appropriate for the research proposed?

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

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

(5) Environment:  Does the scientific environment in which the 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?  For R01 applications, is appropriate bioinformatics expertise and 
support provided?

For R21 applications, the above stated criteria are reviewed but it will be 
noted that the R21 is a developmental/exploratory grant mechanism that is used 
for high risk/high impact projects to generate preliminary data to develop 
novel hypotheses.  Therefore, review standards for preliminary data and past 
performance are not applicable for this mechanism.

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 

o The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project 
proposed in the application.


Letter of Intent Receipt Date:    February 1, 2002
Application Receipt Date:         February 19, 2002
Peer Review Date:                 May 2002
Council Review:                   August 2002
Earliest Anticipated Start Date:  August 2002


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.


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Claudia Thompson, Ph.D.
Scientific Program Administrator
Chemical Exposure and Molecular Biology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
79 T.W. Alexander Drive, Building 4401, MD EC-21
Research Triangle Park, NC  27709
Telephone:  (919) 541-4638
FAX:  (919) 316-4606

Direct inquiries regarding review issues to:

Linda Bass, Ph.D.
Scientific Review Administrator
Scientific Review Branch
Office of Program Operations
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-30
79 TW Alexander Drive, Building 4401
Research Triangle Park, NC  27709
Phone:  (919) 541-1307
Fax:  (919) 541-2503

Direct inquiries regarding fiscal matters to:

Dwight Dolby 
Grants Management Specialist
Grants Management Branch
Office of Program Operations
National Institute of Environmental Health Sciences
P.O. Box 12233
79 T.W. Alexander Drive, Building 4401, MD-EC22
Research Triangle Park, NC  27709
Telephone:  (919) 541-7824
FAX:  (919) 541-2860


This program is described in the Catalog of Federal Domestic Assistance No. 
93.113 and 93.114.  Awards are made under authorization of Sections 301 and 
405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies and Federal Regulations 42 CFR 52 and 
45 CFR Parts 74 and 92.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-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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