and Human Services (HHS)
EXPIRED
COMPLEX FORMATION IN HORMONAL REGULATION OF GENE EXPRESSION
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
THIS PA CONTAINS THE FOLLOWING INFORMATION
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
PURPOSE OF THIS PA
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.
RESEARCH OBJECTIVES
Background
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
genes.
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
expression.
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
intervention.
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
propagation
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-
independence
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)
including:
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
behavior.
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
mechanisms.
MECHANISM(S) OF SUPPORT
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
http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if
you are submitting an application with direct costs in each year of $250,000
or less, use the modular format. Otherwise follow the standard instructions
in the PHS 398 form.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals,
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with their institution to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH programs.
WHERE TO SEND INQUIRIES
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
to:
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
Email: [email protected]
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
E-mail: [email protected]
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
E-mail: [email protected]
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
Email: [email protected]
o Direct your questions about financial or grants management matters relevant
to NIDDK to:
Florence Danshes
Senior Grants Management Specialist
Grants Management Branch, DEA
NIDDK
Democracy II, Room 734
Bethesda, MD 20892
Telephone: (301) 594-8861
FAX: (301) 480-3504
Email: [email protected]
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
Email: [email protected]
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
Email: [email protected]
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
Email: [email protected]
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). The PHS 398 is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 710-0267,
Email: [email protected].
APPLICATION RECEIPT DATES: Applications submitted in response to this program
announcement will be accepted at the standard application deadlines, which
are available at http://grants.nih.gov/grants/dates.htm, and include February
1, June 1, and October 1. These application deadlines are also indicated in
the PHS 398 application kit.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:
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 http://grants.nih.gov/grants/funding/phs398/phs398.html
includes step-by-step guidance for preparing modular grants. Additional
information on modular grants is available at
http://grants.nih.gov/grants/funding/modular/modular.htm.
SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:
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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.
SPECIFIC INSTRUCTIONS FOR R21 APPLICATIONS:
Specific instructions for the R21 may be found at
http://grants1.nih.gov/grants/guide/pa-files/PA-00-073.html. All
applications must adhere to the NIMH R21 instructions.
SENDING AN APPLICATION TO THE NIH:
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
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.
PEER REVIEW PROCESS
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
(http://www.csr.nih.gov/refrev.htm) 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
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In
the written comments, reviewers will be asked to discuss the following
aspects of your application in order to judge the likelihood that the
proposed research will have a substantial impact on the pursuit of these
goals:
o Significance
o Approach
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these criteria
in assigning your application"s overall score, weighting them as appropriate
for each application. Your application does not need to be strong in all
categories to be judged likely to have major scientific impact and thus
deserve a high priority score. For example, you may propose to carry out
important work that by its nature is not innovative but is essential to move
a field forward.
(1) SIGNIFICANCE: Does your study address an important problem? If the aims
of your application are achieved, how do they advance scientific knowledge?
What will be the effect of these studies on the concepts or methods that
drive this field?
(2) APPROACH: Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project? Do you acknowledge potential problem areas and consider alternative
tactics?
(3) INNOVATION: Does your project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does your project challenge
existing paradigms or develop new methodologies or technologies?
(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out
this work? Is the work proposed appropriate to your experience level as the
principal investigator and to that of other researchers (if any)?
(5) ENVIRONMENT: Does the scientific environment in which your work will be
done contribute to the probability of success? Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of institutional
support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, 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.
AWARD CRITERIA
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
REQUIRED FEDERAL CITATIONS
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD:
Research components involving Phase I and II clinical trials must include
provisions for assessment of patient eligibility and status, rigorous data
management, quality assurance, and auditing procedures. In addition, it is
NIH policy that all clinical trials require data and safety monitoring, with
the method and degree of monitoring being commensurate with the risks (NIH
Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts,
June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:
It is the policy of the NIH that women and members of minority groups and
their sub-populations must be included in all NIH-supported clinical research
projects unless a clear and compelling justification is provided indicating
that inclusion is inappropriate with respect to the health of the subjects or
the purpose of the research. This policy results from the NIH Revitalization
Act of 1993 (Section 492B of Public Law 103-43).
All investigators proposing clinical research should read the AMENDMENT "NIH
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research - Amended, October, 2001," published in the NIH Guide for Grants and
Contracts on October 9, 2001
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html)
, a complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm
The amended policy incorporates: the use of an NIH definition of clinical
research, updated racial and ethnic categories in compliance with the new OMB
standards, clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398, and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a)
all applications or proposals and/or protocols must provide a description of
plans to conduct analyses, as appropriate, to address differences by
sex/gender and/or racial/ethnic groups, including subgroups if applicable,
and b) investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:
The NIH maintains a policy that children (i.e., individuals under the age of
21) must be included in all human subjects research, conducted or supported
by the NIH, unless there are scientific and ethical reasons not to include
them. This policy applies to all initial (Type 1) applications submitted for
receipt dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines" on the inclusion of children as participants in
research involving human subjects that is available at
http://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:
NIH policy requires education on the protection of human subject participants
for all investigators submitting NIH proposals for research involving human
subjects. You will find this policy announcement in the NIH Guide for Grants
and Contracts Announcement, dated June 5, 2000, at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
HUMAN EMBRYONIC STEM CELLS (hESC):
Criteria for federal funding of research on hESCs can be found at
http://grants.nih.gov/grants/stem_cells.htm and at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only
research using hESC lines that are registered in the NIH Human Embryonic Stem
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).
It is the responsibility of the applicant to provide the official NIH
identifier(s)for the hESC line(s)to be used in the proposed research.
Applications that do not provide this information will be returned without
review.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The
Office of Management and Budget (OMB) Circular A-110 has been revised to
provide public access to research data through the Freedom of Information Act
(FOIA) under some circumstances. Data that are (1) first produced in a
project that is supported in whole or in part with Federal funds and (2)
cited publicly and officially by a Federal agency in support of an action
that has the force and effect of law (i.e., a regulation) may be accessed
through FOIA. It is important for applicants to understand the basic scope
of this amendment. NIH has provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this PA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the
application. In addition, applicants should think about how to structure
informed consent statements and other human subjects procedures given the
potential for wider use of data collected under this award.
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 http://www.health.gov/healthypeople.
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 http://grants.nih.gov/grants/policy/policy.htm
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.
Weekly TOC for this Announcement
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