Full Text PA-97-001
 
STEROID RECEPTOR STRUCTURE: FUNCTIONAL CONSIDERATIONS
 
NIH GUIDE, Volume 25, Number 34, October 11, 1996
 
PA NUMBER: PA-97-001
 
P.T. 34

Keywords: 
  Receptors 
  Steroids 

 
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute on Aging
 
PURPOSE
 
The objective of this initiative is to elicit grant submissions that
focus on integrating structural with functional information about the
receptors in the steroid/thyroid/retinoid superfamily, including the
orphan receptors for which no known ligands have been identified.
Also referred to as nuclear receptors, the identification and
characterization of the receptors for many of these hormones has
revealed several examples of mutations in key domains or alterations
in function which have been linked to human diseases, including
vitamin D-dependent rickets, thyroid hormone resistance, and androgen
resistance syndrome.  In addition, hormones and their receptors in
this large superfamily have been linked to breast, prostate (and
other) cancers, osteoporosis, obesity, diabetes, and other diseases
or disorders.  Finally, agonists and/or antagonists of
steroid/thyroid/retinoid hormones may have clinical utility for the
prevention or treatment of diseases with significant health relevance
to women, including breast cancer and osteoporosis.
 
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,
Steroid Receptor Structure:  Functional Considerations, is related to
the priority area of chronic disabling conditions.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as principal investigators.
 
MECHANISM OF SUPPORT
 
Support for this Program Announcement will be through the NIH
research project grant (R01) and FIRST (R29) award.  Applicants will
be responsible for the planning, direction, and execution of the
proposed project.  The award of grants in response to this PA is also
contingent upon the availability of funds.  Awards will be
administered under PHS grants policy as stated in the PHS Grants
Policy Statement (rev. 4/94).
 
Applications from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator should be included
with the application.
 
RESEARCH OBJECTIVES
 
Background
 
The receptors for hormones in the steroid/thyroid/retinoid supergene
family are transcription factors which bind to target sequences in
the regulatory regions of hormone-sensitive genes to enhance or
suppress their transcription.  These receptors have evolutionarily
conserved similarities in a series of discrete structural domains,
including a ligand binding domain (LBD), a DNA binding domain (DBD),
a dimerization domain, and one or more trans-activation domain(s)
(AF-1/AF-2). While most members of this family have well
characterized ligands, others have no known ligand(s).  These
"orphan" receptors often have domains with sequences that resemble
LBDs suggesting that ligands do exist.  In other instances, the
absence of consensus LBDs suggests that ligand binding is not a
requisite of function.  Upon ligand binding most of the receptors in
this supergene family form either homo- or hetero-dimers, which bind
to discrete regulatory regions of the promoters of target genes
called hormone response elements (HRE).  There is also a subset of
members of the family which bind DNA as monomers. Binding to DNA may
occur with or without ligand and may result in repression or
enhancement of gene expression in a cell/promoter context.  More
recently it has become evident that additional nuclear accessory
proteins are required to effect receptor-dependent repression or
activation of gene expression.  The structure of the receptor, the
HRE, and the presence/absence of accessory proteins all represent key
determinants of the final effect on expression of target genes. New
information is developing at a rapid pace delineating the
three-dimensional structure of these receptors.  To date, the x-ray
crystallographic structure has been solved for the LBD of the thyroid
receptor, the retinoic X receptor (RXR)gamma, and the peroxisome
proliferator-activated receptor (PPAR)gamma. Similarities in
conserved regions of other receptors, including the estrogen receptor
and the vitamin D receptor, have allowed models to be created which
putatively assign key amino acid residues roles in ligand binding and
regulation of transcription activation domains.  Such information is
increasingly important as a guide for the development of compounds
which can act as full or partial agonists, or antagonists in a
therapeutic context.  Therefore, it is important to integrate
emerging and developing information about receptor structure with
function of these receptors in cell and promoter-specific contexts.
 
The long-term goal of this initiative is to increase basic
understanding of the receptors in this hormone superfamily to allow
for development of specific analogs, partial agonists, or antagonists
with clinical significance in the treatment of disease (e.g.,
osteoporosis, obesity, breast or prostate cancer).  This initiative
is therefore designed to elicit grant submissions which focus on the
structure of steroid/thyroid/retinoid (nuclear) receptors, including
the orphan receptors for which no known ligand has been identified,
and the implications of this structural information for understanding
function.
 
Research Objectives and Scope
 
The major areas of interest and potential that have been identified
relevant to this program announcement are the following:
 
o  Effects of binding of agonists/antagonists to steroid receptors on
structure/function of the receptor
 
o  Role(s) of cytosolic accessory proteins in three-dimensional
folding, subcellular processing, activation/inactivation of steroid
receptors
 
o  Role(s) of nuclear accessory proteins in mediating proper
interaction(s) of liganded or unliganded nuclear receptors with
hormone response elements and/or components of the transcriptional
apparatus
 
o  Effects of structural or mutational alterations in receptor
structure on cell/promoter specificity of the receptor: effects of
homo- or hetero-dimerization and/or HRE spacing and DNA bending on
transactivation
 
o  Components of the structure of steroid receptors and/or the HRE
which have a role in determining the cell, tissue, or promoter
specificity of function
 
While these areas of interest are representative of the intended
scope, the general focus should be on developing an understanding and
integration of structure and function of steroid/thyroid/retinoid
receptors. Applications addressing changes in the structure and
function of these receptors as a direct consequence of aging may be
relevant to the National Institute on Aging.
 
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) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 20, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
 
Investigators also may obtain copies of the policy 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. 5/95) 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 Grants Information Office, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/435-0714, email: asknih@odrockm1.od.nih.gov.
 
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.
 
Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
The completed original application and five legible copies must be
sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications that are complete
will be evaluated for scientific and technical merit by an
appropriate peer review group convened in accordance with 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
 
o  scientific, technical, or medical significance and originality of
proposed research;
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
 
o  availability of the resources necessary to perform the research;
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
 
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, 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 approved
applications assigned to the NIDDK, NIAMS, or NIA.  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 issues to:
 
Ronald N. Margolis, Ph.D.
Endocrinology Section
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 5AN-12J
45 Center Drive
Bethesda, MD  20892-6600
Telephone:  (301) 594-8819
FAX:  (301) 480-3503
Email: rm76f@nih.gov
 
William Sharrock, Ph.D.
Bone Biology Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-43E
45 Center Drive, MSC 4500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5055
FAX:  (301) 480-4543
Email:  william_sharrock@nih.gov
 
Frank Bellino, PhD
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:  bellinof@gw.nia.nih.gov
 
Direct inquiries regarding fiscal and administrative matters to:
 
Kim Law
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 6AS-49A
45 Center Drive
BETHESDA, MD 20892-6600
Telephone:  (301) 594-8869
 
Vicki Maurer
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS-49A
45 Center Drive, MSC 4500
Bethesda, MD  20892-6500
Telephone:  (301) 594-3504
FAX:  (301) 480-4543
Email:  vicki_maurer@nih.gov
 
Robert Pike
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  28092-9205
Telephone:  (301)  496-1472
FAX:  (301) 402-3672
Email:  pikeb@gw.nia.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.847 (NIDDK), No. 93.846 (NIAMS), and No. 93-866
(NIA).  Awards are 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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