ANDROGEN RECEPTOR IN PROSTATE GROWTH AND CANCER
RELEASE DATE: April 1, 2002
RFA: DK-02-031
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Aging
LETTER OF INTENT RECEIPT DATE: October 16, 2002
APPLICATION RECEIPT DATE: November 14, 2002
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:
PURPOSE OF THIS RFA
This RFA seeks applications that will foster greater understanding of
the role of the androgen receptor (AR) in carrying out the signaling
program that reflects androgen action in the prostate gland. The long-
term goal is to better our knowledge of the role of androgens, and the
AR, in growth and development of the prostate, and/or development and
progression of prostate cancer.
RESEARCH OBJECTIVES
Background
In a recent NIDDK RFA (DK-01-008 "Role of Hormones and Growth Factors
in Prostate Cancer") grant applications were solicited to explore the
underlying mechanism(s) of action of hormones and growth factors in the
regulation of prostate development, growth and tumorigenesis. While
this initiative resulted in the funding of major new projects,
significant scientific opportunities remain to be exploited.
Advances in the nuclear hormone receptor (NR) superfamily, of which the
androgen receptor is a member, have revealed a complex pattern of
hormone action in target tissues and cells in response to hormone
(ligand). NRs are ligand-dependent and independent transcription
factors, with roles in development, reproduction, metabolism, and
disease. For many of the known NRs, including the steroid receptor
subfamily (ER, PR, GR, and AR), evidence now points to formation of
large, multicomponent complexes in the nucleus, at the
promoter/enhancer region of target genes, to effect regulation of
expression. The complexes may include coactivators (SRC-1, -2, -3),
corepressors (NCoR, SMRT), RNA transcripts (SRA), histone acetylases
(HAT), or deacetylases (HDAC), methylases (CARM1), components of the
RNA polymerase machinery, and chromatin remodeling factors (ACTR).
Various combinatorial groupings of these factors appear to be essential
for expression of genes in a regulated and specific manner. Examples
include HDACs that depend on the presence of a specific co-repressor
(Fishcle et al., Mol. Cell 9:45-57, 2002), or enhancers (e.g. the POU
domain transcription factor, Oct-1) that recruit specific coactivators
(Gonzalez and Robins, JBC 276: 6420-6428, 2001). Importantly, some
factors when present at inappropriate levels have been implicated in
malignant transformation, including overexpression of the SRC-2 family
member AIB(amplified in breast cancer)1 coactivator in some tumors of
breast, and the fusion protein ETO (eight:to:twentyone), a
hematopoietic transcription factor fused to a NR (RAR) creating an
aberrant transcription factor that recruits high levels of corepressor
in some leukemias. Exciting use of this basic knowledge has led to
development of an RAR ligand that relieves repression and leads to
differentiation of the tumor cells, resulting in remission. In these
examples alterations in the combinatorial complex subverts the normal
program of regulation leading or contributing to tumor formation.
For the AR, new evidence suggests that receptor interaction with other
structural and signaling molecules in prostate, including caveolin (Lu
et al. JBC 276: 13442-51, 2001) or Smads (Kang et al. PNAS 98:30181-23,
2001), affects the ability of AR to regulate gene expression.
Signaling cross-talk involving novel protein kinases (Yang et al. JBC
276:15345-53, 2001), such as PAK6, or interaction with elements of the
cytoskeleton important for nuclear localization (Tyagi et al. Mol.
Endocrinol. 14:1162-74, 2000), may also be important for hormone
action. The net result has been to sharpen our focus on the AR and how
it functions to carry out a program of gene regulation in prostate in
response to androgens. Research is needed to better understand how
this program functions to regulate normal growth of the prostate and
how it may be subverted in prostate cancer.
The revolution in genomics and proteomics has fostered a multitude of
new approaches, such as array technology, and high throughput mass
spectroscopy, to identify genes that are up or down regulated at key
times in the lifecycle of a cell or tissue. Understanding the
composition and function(s) of higher order regulatory complexes in
normal physiology and disease development/progression represents an
important scientific opportunity. By utilizing functional genomics it
may be possible to use computational approaches to dissect known
regulatory pathways and uncover unknown components (Michelson et al.
PNAS 99:546-548, 2002) in a way that allows greater integration of
information and reveal hitherto unrecognized relevance to disease. The
NIDDK has attempted to foster the application of these technologies to
problems in its core mission through a Technology Center initiative
(DK-01-019 "NIDDK Biotechnology Centers Initiative") in which resources
were provided to develop technology cores to assist funded
investigators apply new approaches to their research. This seed money
has fostered development of operational technology centers, including
microarray cores, to subsequently operate on an independent basis. The
opportunity now exists to integrate new technologies with emerging
concepts of hormone action to explore the underlying mechanism(s) of
prostate growth, tumor formation and progression.
Scope
In order to achieve the objectives of this RFA it may be necessary to
foster collaborative projects with expertise in molecular
endocrinology, genomics, proteomics, array technology, developmental
biology, cancer biology, pharmacology, or physiology. Specific
questions that require further research include:
Regulation of gene expression in prostate in response to androgens
Modulation of the androgen signaling program by other signals (cross-
talk) and potential role in growth and tumorigenesis
Determination of the components of AR-nuclear accessory protein
complexes responsible for determination of specificity and regulation
of gene expression
Role of aberrant signaling in tumor progression and possible role(s) in
development of androgen-independent tumor growth
Identification of AR target genes up- and/or down regulated by hormone
in normal and transformed prostate through use of DNA arrays, high
throughput proteomics, in silico computational, or other means
Development of systems to identify and/or utilize model androgen-
sensitive genes for studies into the mechanism of action of the AR
Determination of key AR-cofactor interaction sites as potential targets
for development of therapeutic intervention
Elucidation of the mechanism(s) of action of selective receptor
modulators (SRMs) with potential AR antagonist or selective partial
agonist activity
In addition, the National Institute on Aging (NIA) is interested in
funding applications focused on age-related changes in androgen action,
androgen receptor signaling pathway and interactions with other
signaling pathways, AR-dependent gene expression, and other androgen-
and AR-dependent processes that may impact prostate growth in middle-
aged and older men leading to their high risk for prostate- and
urinary-associated health problems. This research is very important
for understanding potentially negative health consequences of
testosterone replacement in elderly men. The NIA is also interested in
funding research relevant to age-related changes in androgen- and AR-
associated actions in minority populations for which substantial health
disparities exist in the incidence and prevalence of prostate cancer,
and for which studies have suggested that genetic differences in AR
structure may exist.
These examples do not preclude other important questions relevant to
the AR that can be posed by investigators responding to this
initiative. In order to accomplish several of the above objectives,
use of existing NIDDK Biotechnology Centers is encouraged.
MECHANISM OF SUPPORT
This RFA 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. This RFA is a one-time solicitation.
Future unsolicited, competing-continuation applications based on this
project will compete with all investigator-initiated applications and
will be reviewed according to the customary peer review procedures. The
anticipated award date is July 1, 2003.
This RFA uses just-in-time concepts. It also uses the modular and 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.
FUNDS AVAILABLE
NIDDK intends to commit $3M (Total costs) in FY 03 to fund 12 to 15 new
grants in response to this RFA. The NIA will commit an additional
$250,000 (Total costs) to fund 1-2 applications. An applicant may
request a project period of up to 4 years (2 for the R21) per year.
While the budgets for the R01 are not capped, for the R21 a limit of
$100,000/year is in place. Because the nature and scope of the proposed
research will vary from application to application, it is anticipated
that the size and duration of each R01 award will also vary. Although
the financial plans of the IC(s) provide support for this program,
awards pursuant to this RFA are contingent upon the availability of
funds and the receipt of a sufficient number of meritorious
applications. At this time, it is not known if this RFA will be
reissued.
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 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 encouraged to apply to NIH programs.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity
to answer questions from potential applicants. Inquiries may fall into
three areas: scientific/research, peer review, and financial or grants
management issues:
o Direct your questions about scientific/research issues relevant to
NIDDK to:
Ronald Margolis, Ph.D.
Senior Advisor, Molecular Endocrinology
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Democracy II, Room 6107
Bethesda, MD 20892-5460
Telephone: (301) 594-8819
FAX: (301) 435-6047
Email: rm76f@nih.gov
o Direct your questions about scientific/research issues relevant to
NIA to:
Frank Bellino, Ph.D.
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231 MSC 9205
Bethesda, MD 20892-9205
Telephone: (301) 496-6402
FAX: (301) 402-0010
Email: fb12a@nih.gov
o Direct your questions about peer review issues to:
Dr. Francisco Calvo
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases 2
Democracy, Room 752
Bethesda, MD 20892
Telephone: (301) 594-8897
FAX: (301) 480-3505
Email: CalvoF@extra.niddk.nih.gov
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: fd39j@nih.gov
o Direct your questions about financial or grants management matters
relevant to NIA to:
Jeff Ball
Grants Management Specialist
National Institute on Aging
7201 Wisconsin Ave., Suite 2N212
Bethesda, MD 20892-9205
Telephone: (301) 496-1472
FAX: (301) 492-3672
Email: ballj@nia.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that
includes the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review
workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning
of this document. The letter of intent should be sent to:
Dr. Francisco Calvo
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Democracy II, Room 752
Bethesda, MD 20892
Telephone: (301) 594-8897
FAX: (301) 480-3505
Email: fc15y@nih.gov
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: GrantsInfo@nih.gov.
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 R21 GRANT APPLICATIONS: Use of the R21 grant
mechanism for this RFA is intended for pilot and feasibility studies
related to the scope of this solicitation. Applicants should use the
PHS398 application (as above), but should not exceed 15 pages for Items
a-d. All tables, graphs, figures, diagrams, and charts must be included
within the 25-page limit. Applicants are encouraged to be succinct and
are reminded that there is no necessity to use all 15-pages allotted to
Items a-d of the Research Plan. All other instructions listed for the
PHS398 application should apply.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev.
5/2001) application form must be affixed to the bottom of the face page
of the application. Type the RFA number on the label. Failure to use
this label could result in delayed processing of the application such
that it may not reach the review committee in time for review. In
addition, the RFA title and number must be typed on line 2 of the face
page of the application form and the YES box must be marked. The RFA
label is also available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten
original of the application, including the Checklist, and three 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)
At the time of submission, two additional copies of the application
plus any appendix material must be sent to:
Dr. Francisco Calvo
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Democracy II, Room 752
Bethesda, MD 20892
Telephone: (301) 594-8897
FAX: (301) 480-3505
Email: fc15y@nih.gov
APPLICATION PROCESSING: Applications must be received by the
application receipt date listed in the heading of this RFA. If an
application is received after that date, it will be returned to the
applicant without review.
The Center for Scientific Review (CSR) will not accept any application
in response to this RFA that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application. The CSR will not accept any application that is
essentially the same as one already reviewed. This does not preclude
the submission of substantial revisions of applications already
reviewed, but such applications must include an Introduction addressing
the previous critique.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the (IC). Incomplete applications will be
returned to the applicant without further consideration. If the
application is not responsive to the RFA as determined by NIDDK program
staff, CSR staff may contact the applicant to determine whether to
return the application to the applicant or submit it for review in
competition with unsolicited applications at the next appropriate NIH
review cycle.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIDDK in accordance with the review
criteria stated below. As part of the initial merit review, all
applications will:
o Receive a written critique
o Undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications
under review, will be discussed and assigned a priority score
o Receive a second level review by the National Diabetes and Digestive
and Kidney Diseases Advisory Council.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.
In the written comments, reviewers will be asked to discuss the
following aspects of 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?
SPECIFIC CRITERIA FOR REVIEW OF R21 APPLICATIONS: R21 applications
submitted to this RFA should reflect pilot and feasibility studies with
a high degree of potential significance and innovation, and for which
there may be more risk and less preliminary data than for a full R01
submission.
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your
application will also be reviewed with respect to the following:
o 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.
o 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)
o BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: October 16, 2002
Application Receipt Date: November 14, 2002
Peer Review Date: March/April 2003
Council Review: May 2003
Earliest Anticipated Start Date: July 1, 2003
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
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_20
01.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 RFA 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, and 93.866 for NIA,
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 and 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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