RELEASE DATE:  April 26, 2002

PA NUMBER:  PA-02-100

EXPIRATION DATE:  05/01/2005 unless reissued.
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Mental Health
National Institute on Aging
National Cancer Institute


o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


This initiative represents a reissue of PA99-111 (Coactivators and 
Corepressors in Gene Expression).  The original PA was based on an NIDDK 
Workshop ("Co-Activators and Co-Repressors in Gene Expression," December 15-
16, 1998) and was designed to stimulate research to address the fundamental 
underlying mechanisms by which nuclear accessory proteins, such as 
coactivators and corepressors, mediate signaling through hormone receptors at 
the level of the regulation of gene expression.  The reissued PA seeks to 
exploit and expand upon advances made since then in this, and other related 
areas and refine the role of higher order complex formation in effecting 
hormonal regulation of gene expression.  



Regulation of hormone action involves both short- and long-term functions 
expressed in minutes-to-hours as either rapid changes in cellular metabolism 
or change in gene expression.  At the level of gene expression numerous 
cytoplasmic and nuclear accessory proteins have been implicated in mediating 
hormone action.  Co-repressors and co-activators are important examples that 
represent classes of nuclear accessory proteins that also include elements of 
the basal and regulated transcription machinery in cells.  An earlier NIDDK 
workshop entitled: "Co-Activators and Co-Repressors in Gene Expression" 
(December 15-16, 1998) highlighted the importance of emerging information on 
the roles of nuclear accessory factors in the regulation of signaling at the 
level of transcription. Their ultimate role is in mediating the action of 
transcription factors, representing hormone receptors or the end effectors of 
hormone receptors, in enhancing or suppressing the expression of specific 

The nuclear hormone superfamily comprises soluble hormones whose receptors 
are present in the cytoplasm and the nucleus of most cells.  Members of this 
large hormone superfamily (steroid hormones: adrenal glucocorticoids, 
mineralocorticoids, estrogen, progesterone, androgen; nuclear hormones:  
thyroid, vitamins A/D; orphan nuclear receptors: PPAR, LXR, CAR) have wide-
ranging effects on metabolism, development, reproduction, and sexual 
function.  The receptors for the nuclear receptor superfamily function 
primarily as transcription factors in the nucleus to either suppress or 
enhance gene expression through effects on DNA transcription.  In both 
instances, the formation of higher order complexes with nuclear accessory 
proteins is an important part of the process of activation of gene 

Cell surface receptors (CSR) are receptors whose ligand is extracellular, 
with binding to a receptor anchored in or spanning the membrane.  Several 
classes of CSR exist, including the G-protein coupled receptors (GPCR), 
Ser/Thr kinase receptors, growth factor receptors, and cytokine receptors.  
All involve initiation of signaling cascades within the cell that amplify and 
propagate the signal.  End points of signaling through CSRs may also include 
change in gene expression through the activation or subcellular translocation 
of transcription factors. While the transcription factor is not the receptor, 
itself, the net result is the same. Here, too, complex formation at or near 
promoter regions is essential to regulation of gene expression.

Nuclear accessory proteins expressing histone acetyltransferase (HAT) or 
deacetyltransferase (HDAC) activities have been implicated in acetylation or 
deacetylation of core histones, thus altering the accessibility of DNA to 
elements of the complex and including the RNA polymerase machinery, itself.  
Other factors required for chromatin remodeling, such as methytranferases, 
also alter accessibility, with potential effects on cell cycle control, 
mitosis, meiosis, and other functions of chromatin.  Still others serve to 
link the receptor, or transcription factor, when bound to DNA, to the 
transcriptional machinery to complete formation of a large complex 
(enhanceosome) and regulate gene expression.  In the case of CSRs the 
effector is a transcription factor activated as the end result of signaling 
cascades.  Thus, combinatorial complexes that form, dissolve, and re-form, 
contribute to specificity and overall regulation with altered levels of 
expression, mutation or posttranslational modification of constituent 
components also contributing to disease development and/or progression. As a 
consequence, these factors have also now become targets for therapeutic 

While considerable progress has been made, it remains to be determined how 
the formation of higher order complexes at the enhancer/promoter region of 
target genes is involved in defining specificity of hormone action at the 
level of specific genes, cells, and tissues.  Also of importance is the 
potential role(s) complex formation may play in the development of endocrine 
organs or of diseases relevant to NIDDK, such as diabetes, obesity, 
osteoporosis, and prostate cancer.

Thus, the specific objectives of this research solicitation include:

o  Role of coactivators/corepressors in the regulation of tissue-specific 
gene expression

o  Role of cytoplasmic factors in hormone or receptor processing and/or 
signal propagation to the nucleus

o  Identification of model systems that allow for study in vitro or in vivo 
of gene expression 

o  Role(s) of nuclear accessory proteins in regulation of nuclear hormone 
action in target cells

o  Novel factor(s) associated with hormone action involved in disease 
genesis, including breast and prostate cancer, obesity, insulin resistance, 
diabetes, and osteoporosis

o  Selective Receptor Modulators (SRM) with potential effects on disease 
development and/or progression

o  Structural biology of receptor/interacting protein and/or cofactor 
interaction focusing on interactions with other receptor interacting 
proteins, co-activators or co-repressors, the ligand, or HREs in signal 

o  Role(s) of chaperone proteins in regulating receptor function and/or 
interaction with ligands or nuclear accessory proteins, including nuclear 
localization and/or proteasomal degradation

o  Signaling cross-talk between classes of receptors and cytoplasmic and/or 
nuclear accessory proteins and effects on regulation of gene expression and 
disease initiation/progression

o  Molecular mechanisms by which Breast and Prostate tumors acquire hormone-

This suggested scope is not meant to be comprehensive or to restrict ideas to 
these particular concerns. It does, however, represent issues relevant to the 
mission of the NIDDK.

The National Institute of Mental Health (NIMH) is also interested in the 
basic processes regulating nuclear and cytosolic hormone and receptor 
signaling outlined above pertaining to the central nervous system (CNS) 

o Genetic and cellular mechanisms by which hormone receptors and accessory 
proteins regulate signaling in the intact central nervous system and in 
cellular models of brain hormone action. 

o CNS-specific actions of hormones on brain gene expression, brain 
development (through  puberty, synaptic plasticity, neural function and 

o Studies directed toward elucidating the role of hormones in determining sex 
differences in neuropsychiatric disorders.

Hormonal replacement therapies or tissue-specific hormonal 
agonists/antagonists are used in middle-aged and elderly people, to return 
levels of selected hormones back to youthful levels as those hormonal levels 
decrease with age in the expectation that these treatments will provide 
health-protective benefits.   However, there is little information available 
regarding age-dependent altered tissue responses to natural hormones or 
tissue-specific analogues to support the hypothesis that the biologic 
response to hormones is similar in young and older individuals. Thus, the 
National Institute on Aging (NIA) is interested in supporting research whose 
scope includes study of underlying mechanisms of age-related changes in gene 
expression mediated by hormonal signaling through receptors and cellular 
accessory proteins involved in coupling the receptors to gene expression 


This PA will use the NIH R01 and R21 award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project. For the R21 there is a limit of 2 years at $100,000/year in 
requested support.  This PA uses just-in-time concepts.  It also uses the 
modular as well as the non-modular budgeting formats (see  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 standard instructions 
in the PHS 398 form.


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


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.   


We encourage your inquiries concerning this PA and welcome the opportunity 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research, and financial or grants management issues:

o Direct your questions about scientific/research issues relevant to NIDDK 

Ronald Margolis, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
2 Democracy, Room 6107
Bethesda, MD  20892
Telephone:  (301) 594-8819
FAX:  (301) 435-6047

o Direct your questions about scientific/research issues relevant to NIMH to:
Hemin Chin  Ph.D. 
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health 
6001 Executive Blvd. Room 7190, MSC 9643
Bethesda, MD 20892-9643 
Rockville, MD 20852 (for courier/overnight mail service) 
Telephone: 301-443-1706 
FAX: 301-443-9890 

o Direct your questions about scientific/research issues relevant to NIA to:

Frank Bellino, Ph.D.
Endocrinology Program Administrator
Deputy Associate Director
Biology of Aging Program
National Institute on Aging
Gateway Bldg., Suite 2C231
Bethesda, MD  20892-9205
Telephone: 301 496-6402
FAX: 301 402-0010

o Direct your questions about scientific/research issues relevant to NCI to:

Neeraja Sathyamoorthy, Ph.D.  
Program Director  
Tumor Biology & Metastasis Branch  
Division of Cancer Biology  
National Cancer Institute 
6130 Executive Boulevard EPN 5036 
Rockville MD 20892 
Phone: 301-435-1878  
Fax: 301-480-0864 

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

Florence Danshes
Senior Grants Management Specialist
Grants Management Branch, DEA
Democracy II, Room 734
Bethesda, MD  20892
Telephone:  (301) 594-8861
FAX:  (301) 480-3504

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

Ms. Carol Robinson
Grant Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6118, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-3858
FAX: (301) 443-6885

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

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672

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

Bill Wells
Grants Administration Branch
EPS Room 243
6130 Executive Boulevard
Rockville MD 20892
Phone: 301-496-8796


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at, and include February 
1, June 1, and October 1.  These application deadlines are also indicated in 
the PHS 398 application kit.


Applications requesting up to $250,000 per year in direct costs 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 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at


Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:

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

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at 


Specific instructions for the R21 may be found at  All 
applications must adhere to the NIMH R21 instructions.


Submit a signed, typewritten original of the application, including the 
checklist, and five 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)

APPLICATION PROCESSING: Applications must be received by or mailed on or 
before the receipt dates described at  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 


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
( will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board


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 

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 

(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 

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  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.

INCLUSION:  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 included in the 
section on Federal Citations, below)

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


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

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities



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:  


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 
; 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 


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 


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


Criteria for federal funding of research on hESCs can be found at and at  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see   
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 

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 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.

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 PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.847 for NIDDK, 93.242 for NIMH, 93.866 for 
NIA and 93.396 for NCI and is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.  
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 described at 
under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.

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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