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) 435-0714, 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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