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: rm76f@nih.gov 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: hc7v@nih.gov 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: fb12a@nih.gov 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: ns61r@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 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: cr2092@nih.gov 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: lw17m@nih.gov 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: wellsw@mail.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. 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.
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