CO-ACTIVATORS AND CO-REPRESSORS IN GENE EXPRESSION

Release Date:  June 14, 1999

PA NUMBER:  PA-99-111

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Environmental Health Sciences
National Institute of Child Health and Human Development
National Institute on Aging
National Institute of Arthritis, Musculoskeletal, and Skin Diseases
National Institute of Mental Health

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

This initiative stems from a recent NIDDK workshop in molecular endocrinology
entitled: "Co-Activators and Co-Repressors in Gene Expression (December 15-16,
1998) and is designed to stimulate research that addresses the fundamental
underlying mechanisms by which nuclear accessory proteins mediate signaling
through hormone receptors at the level of the regulation of gene expression.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This PA, CO-ACTIVATORS AND CO-REPRESSORS
IN GENE EXPRESSION, is related to the priority area of diabetes.  Potential
applicants may obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and nonprofit
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 investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project
grant (R01) and pilot and feasibility (R21) award mechanisms.  Responsibility
for the planning, direction, and execution of the proposed project will be
solely that of the applicant. The duration of projects submitted in response
to this PA may not exceed 5 years for R01s or 2 years for R21s.  Applications
for R21 grants must request no more than $100,000 direct costs in any one
year.

Specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.  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 Institute staff. 
Refer to instructions under BUDGET INSTRUCTIONS below.  Complete and detailed
instructions and information on Modular Grants can be found at
http://www.nih.gov/grants/funding/modular/modular.htm.

R01 applications that request more than $250,000 direct costs in any year must
use the traditional budget format and PHS 398 application instructions.

Since NICHD and NIAMS do not routinely accept the R21, staff contact prior to
submission is highly recommended.

RESEARCH OBJECTIVES

Summary

Co-repressors and co-activators represent classes of nuclear accessory
proteins that include elements of the basal and regulated transcription
machinery in cells.  A recent NIDDK workshop in molecular endocrinology
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. Transcription factors representing hormone receptors or other
factors recruited by hormone receptors are responsible for enhancing and/or
suppressing the expression of specific genes.

Background

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, such as the class I hormones, including adrenal
glucocorticoids, mineralocorticoids, the sex steroids (estrogen, progesterone,
androgen) and class II hormones, including, thyroid, vitamins A/D, PPAR, and
retinoid X, have wide-ranging effects on metabolism, development,
reproduction, sexual function, and behavior.  The receptors for the nuclear
receptor superfamily function primarily as transcription factors in the
nucleus to either suppress or activate gene expression through effects on DNA
transcription.  In the absence of ligand, nuclear receptors, often bound as
heterodimers (homodimers for the sex steroids) to hormone response elements
(HREs) in the promoter regions of target genes, act to suppress transcription. 
In the presence of ligand, activation can occur.

Cell surface receptors (CSRs) are receptors whose ligand is extracellular, and
binds 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 to amplify and effect the
signal.  End points of signaling through CSRs may also include change in gene
expression through the activation of transcription factors.

Numerous recent findings have implicated several classes of nuclear accessory
proteins which are recruited to the receptor dimer as co-activator or co-
repressor complexes to suppress or activate gene expression at HREs for
nuclear hormone superfamily, and other, receptors.  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 RNA
polymerase machinery.  Other factors required for chromatin remodeling, and
including methyltranferases, also alter accessibility, with potential effects
on cell cycle control, mitosis, meiosis, and other functions of chromatin. 
Still other factors serve to link the nuclear receptor when bound to HRE to
the transcriptional machinery to complete the enhancer role of the nuclear
hormone in regulation of gene expression.  Still other transcription factors
are activated as the end result of signaling cascades through CSRs.  Co-
activators and co-repressors serve integral functions in the formation of
larger scale complexes with HATs and/or HDACS that mediate the actions of
transcription factors on gene expression.

Additional work presented at the "Co-Activator/Co-Repressor" workshop
suggested a role for the relative affinity of binding of co-repressor versus
co-activator complexes in determining whether a particular gene is activated
or not in response to ligand.  Further observations have pointed to mutations
in nuclear accessory proteins and/or nuclear receptors as factors that can
either cause hormone resistance or inappropriate gene expression.  Fusion
proteins, such as the AML-ETO fusion protein in acute myelogenous leukemia,
have been implicated in tumorigenesis. In AML the mechanism of action appears
to be recruitment of co-repressor complexes to block gene transcription
relevant to differentiation of hematopoietic precursors.  In another instance,
mutations in one co-activator, AIB1, have been implicated in breast cancer. 
As a result, these factors have now become targets for therapeutic
intervention.  Thus, the specific objectives of this research solicitation
include but are not limited to:

o  Mechanism of action of nuclear receptors in the regulation of tissue-
specific gene expression;

o  Mechanism of signaling through cell surface receptors that result in
recruitment and/or activation of transcription factors;

o  Model systems that allow for study of in vitro or in vivo gene expression
in target cells;

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

o  Novel factor(s) associated with nuclear hormone action involved in disease
genesis, including breast and prostate cancer, diabetes, neurodegenerative
diseases, mental disorders, and osteoporosis;

o  Analogs, agonists, or antagonists of nuclear hormones with potential
effects on disease development and/or progression;

o  Structural biology of the receptors focusing on interactions with other
receptor interacting proteins, co-activators or co-repressors, the ligand, or
HREs;

o  Role(s) of heat shock, or other chaperone, proteins in regulating receptor
function and/or interaction with ligands or nuclear accessory proteins;

o  Signaling cross-talk between nuclear receptors and/or cell surface
receptors and effects on regulation of gene expression and disease
initiation/progression;

o  Role(s) of hormones/nuclear accessory protein interactions in regulating
events occurring during development, including differentiation of endocrine
organs or tissues;

o  Role(s) of hormones/nuclear accessory protein interactions on neural
functions, brain development and behavior;

In addition:

The National Institute of Environmental Health Sciences (NIEHS) is interested
in understanding how exogenous chemicals, including phytoestrogens, with
hormonal activity alter the activity of endogenous hormone systems via
mechanisms that disrupt cell signaling or cross talk between receptors,
interact with specific receptor subtypes, or alter gene expression at the
molecular level and the role of these changes in the initiation or progression
of diseases.

The National Institute of Child Health and Human Development (NICHD) is
interested in grants whose scope is relevant to issues of reproduction.

The National Institute on Aging (NIA) is interested in grants whose scope
includes study of underlying mechanisms for age-related changes in gene
expression mediated by hormonal signaling through receptors and nuclear
accessory proteins; including age-related changes in responses involving
nuclear accessory proteins with tissue-specific hormonal agonist or antagonist
analogues.

The National Institute of Arthritis, Musculoskeletal, and Skin Diseases
(NIAMS) is interested in applications whose scope falls within the appropriate
referral guidelines.

Finally, applicants are encouraged to discuss in the Significance Section the
potential clinical relevance of their work.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.  This new policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 23, No.
11, March 18, 1994, available on the web at:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.

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
address: http://www.nih.gov/grants/guide/notice-files/not98-024.html.

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

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated
in the application kit.  Application kits are available at most institutional
offices of sponsored research, or may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-
435-0714, email: GrantsInfo@nih.gov.

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
Ă¾time 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 Institute
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used
in applying for these grants, with the modifications noted below.

The program announcement title and number must be typed on line 2 of the face
page of the application form and the YES box must be marked.

Submit the signed, original, single-sided application, including the
Checklist, along with five signed photocopies and five collated sets of
appendix materials 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)

The Center for Scientific Review (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 substantial
revisions of applications already reviewed, but such applications must include
an introduction addressing the previous critique.

BUDGET INSTRUCTIONS

Modular grant applications will request direct costs in $25,000 modules up to
a total direct cost request of $250,000 per year. Applications that request
more than $250,000 in any year must use the traditional PHS 398 application
instructions and not the instructions shown below.

The total direct costs must be requested in accordance with the program
guidelines and the modifications made to the standard PHS 398 application
instructions described below:

PHS 398

o  FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period.  Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398.  It is not required and will not be accepted with the
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page.
(See http://www.nih.gov/grants/funding/modular/modular.htm for sample pages.) 
At the top of the page, enter the total direct costs requested for each year.

o  Under Personnel, list key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000.  List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of key personnel,
and the role on the project.  Indicate whether the collaborating institution
is foreign or domestic.  The total cost for a consortium/contractual
arrangement is included in the overall requested modular direct cost amount. 
(Address whether indirect costs for subcontracts are included in the total
costs for the application.  In general, indirect costs are not included in the
total cost budget for R01s, etc.; however, if an absolute cap exists (e.g.,
centers), indirect costs are usually included in the total costs requested. 
Address whether the subcontract costs should be in modular form or rounded to
the nearest $1000.)

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers to assess each individual's qualifications for a specific role in
the proposed project, as well as to evaluate the overall qualifications of the
research team.  A biographical sketch is required for all key personnel,
following the instructions below. No more than three pages may be used for
each person.  A sample biographical sketch may be viewed at
http://www.nih.gov/grants/funding/modular/modular.htm

Complete the educational block at the top of the form page;
- List positions and any honors;
- Provide information, including overall goals and responsibilities on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o  CHECKLIST - This page should be completed and submitted with the
application.  If the F&A rate agreement has been established, indicate the
type of agreement and the date. It is important to identify all exclusions
that were used in the calculation of the F&A costs for the initial budget
period and all future budget years.

o  The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public Health
Service referral guidelines.  Applications will be evaluated for scientific
and technical merit by scientific review groups convened in accordance with
the standard NIH peer review procedures.  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 applications under review, will be discussed,
assigned a priority score, and receive a second-level review by the
appropriate national advisory council or board.

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, reviewer 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.

o  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?

o  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?

o  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?

o  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)?

o  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?

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

o  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 evaluated.

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

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

The initial review group will also examine the provisions for the protection
of human subjects and the safety of the research environment.

o  Availability of special opportunities for furthering research programs
through the use of unusual talent resources, populations, or environmental
conditions in other countries which are not readily available in the United
States or which provide augmentation of existing U.S. resources.

AWARD CRITERIA

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

o  Quality of the proposed project as determined by peer review;
o  Availability of funds;
o  Program priority.

INQUIRIES

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

Direct inquiries regarding programmatic to:

Ronald Margolis, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8819
FAX:  (301) 435-6047
Email:  rm76f@nih.gov

Jerrold J. Heindel, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 112233
Research Triangle Park, NC
Telephone:  (919) 541-0781
FAX:  (919) 541-5064
Email:  heindelj@niehs.nih.gov

Koji Yoshinaga, Ph.D.
Center for Population Research
National Institute of Child Health and Human Development
Building 61E, Room 8B01
Bethesda, MD 20892-7510
Telephone:  (301) 435-6992
FAX:  (301) 496-0962
Email:  ky6o@nih.gov

Frank Bellino, Ph.D.
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  FB12A@NIH.GOV

William J. Sharrock, Ph.D.
Musculoskeletal Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-37A
45 Center Drive
Bethesda, MD  20892
Telephone:  (301) 594-5055
FAX:  (301) 480-4543
Email:  ws19h@nih.gov

Hemin R. Chin, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7190, MSC 9643
Bethesda, MD 20892-9643
Telephone: (301) 443-1706
FAX:  (301) 443-9890
Email: hemin@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Charlette Kenley
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8847

Melinda B. Nelson
Grants Management Branch
National Institute of Child Health and Human Development
Building 61E, Room 8A17
Bethesda, MD  20892-7510
Telephone:  (301) 496-5482
FAX:  (301) 496-0915
Email:  mn23z@nih.gov

Bob Pike
Grants Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  pikeb@exmur.nia.nih.gov

Vicki L. Maurer
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-37H
45 Center Drive
Bethesda, MD 20892
Telephone: (301) 594-3504
FAX: (301) 480-4543
Email: vm8j@nih.gov

Ms. Diana S. Trunell
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD  20892-9605
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  dtrunell@mail.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.847 (NIDDK), 93-846 (NIAMS), 93.866 (NIA), 93.113 and 93.115 (NIEHS), and
93.864 (NICHD).  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-
158, 42 USC 241 and 285) and administered under PHS grants policies and
Federal Regulations 42 CFR 52 and 45 CFR Part 74.  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 and contract 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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