HPA REGULATION: CROSS-DISCIPLINARY RESEARCH NETWORKS Release Date: November 25, 1998 RFA: MH-99-003 P.T. National Institute of Mental Health Letter of Intent Receipt Date: January 17, 1999 Application Receipt Date: February 17, 1999 PURPOSE The National Institute of Mental Health (NIMH) is committed to the creation of interdisciplinary research to advance understanding of complex mental disorders. To facilitate this commitment, NIMH invites proposals for the formation of cross- disciplinary networks of scientists interested in the role of hypothalamic- pituitary-adrenal axis (HPA) regulation in development and psychopathology. These research networks will allow the formation of novel collaborations among neuroscientists, behavioral scientists, and clinical scientists in order to develop integrative and cutting edge research project grant applications. It is increasingly apparent that the HPA system is a leading model for a biological system that can provide a bridge linking behavior and psychopathology. Moreover, HPA as it relates to biological and behavioral development, is a prime research topic for integration across basic and clinical domains. To foster further integration in this area, NIMH will offer up to $50,000 in direct costs each year for up to two years, to support travel and meeting costs for each scientific network. Networks must include representation from multiple perspectives that at a minimum, span expertise across levels of analysis (e.g., molecular to behavioral), species (including humans), and disciplines (e.g., behavioral science, neuroscience, and psychiatry). 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 Request for Applications (RFA), HPA Regulation: Cross-Disciplinary Research Networks, is related to the priority areas of Mental Health and Mental Disorders. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000/ ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, and laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible, however, foreign components may be included in proposed networks applied for by domestic institutions. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the Small Grant (R03) mechanism. Responsibility for the planning, direction, and execution of the proposed networks will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed two years. Although the nature and scope of the research proposed in response to this RFA may vary, the direct costs requested each year may not exceed $50,000. This RFA is one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Applicants are strongly encouraged to discuss their applications with program staff listed under INQUIRIES prior to the submission. FUNDS AVAILABLE It is estimated that $350,000 (total costs) will be available for the first year of support for the entire program. It is anticipated that up to five awards could be supported by these funds depending on the scientific merit of the applications received. Therefore, all funds may or may not be awarded. RESEARCH OBJECTIVES Background The discovery, more the 25 years ago, of corticosteroid receptors (GCR) in the brain opened important new areas of research on the regulation of many brain- behavior systems. A rich literature has been established in the intervening years on the function of the HPA system, which is the principal biological substrate regulating glucocorticoid secretion. Many brain regions express GCRs, and glucocorticoids influence many brain systems. However, they seem to be primarily associated with responses to environmental challenge and the regulation of circadian functions. Interestingly, research with animals has shown that early manipulations of the HPA system can impair behavioral and neuroendocrine responses to stress in adults. These effects are particularly evident when the early experience involves social impact or trauma. Similarly, other evidence demonstrates that the developing brain is very sensitive to glucocorticoid levels where absence or excessive levels of these steroids can lead to serious effects on brain structure. Furthermore, individual differences in HPA regulation could be involved in the development of psychopathology. For example, higher levels of cortisol have been associated with temperamental inhibition in children (e.g., shyness, fear of novel events). Temperamental inhibition has been implicated as a risk factor for the development of childhood internalizing problems, which can be defined by social withdrawal, anxiety, and depression. Recent research suggests that consistently high levels of cortisol may be predictive of later problems such as anxiety disorder in clinically referred children. Conversely, lower cortisol has been associated with other childhood disorders such as difficulty in regulating anger and attention. Although some of the mechanisms of HPA function and glucocorticoid response are known, the ways in which HPA regulation might be related to the development of various mental disorders is largely unexplained. Examination of these and related questions about HPA regulation are expected to result from interactions within the networks encouraged by this RFA. Scope Behavior, psychopathology, the HPA system, and brain responses to glucocorticoids are each complex issues that have traditionally been studied by investigators in different disciplines. To better understand the relationships between these elements of biology and behavior it may be helpful to form integrated research programs that span multiple levels of analysis. This RFA is intended to begin a process where scientists can overcome barriers to cross-disciplinary research agendas. Scientists interested in the role of HPA regulation in development and psychopathology may propose the formation of networks of individuals across disciplinary fields to form collaborative research agendas. Funds may be requested to support administrative costs for the Network Director, communication costs, travel expenses, evaluation and analysis of data by network members in order to attend and participate in scheduled activities and meetings of the network. The purpose of these activities and meetings will be to refine conceptual frameworks for organizing cross-disciplinary research and identifying which specific questions and possible experiments show the greatest promise for advancement. Moreover, networks are expected to generate creative and well- designed research plans that address questions that benefit from integrative perspectives and form the basis of competitive grant proposals. Investigators are encouraged not to participate in more than one network, although exceptions can be made with appropriate scientific justification. Networks must include representation from multiple disciplines. For example, investigators with expertise in neuroscience, behavioral science, and psychiatry would be highly appropriate. Also, networks must span multiple levels of analysis (e.g., molecular to behavioral) and are strongly encouraged to include expertise in animals and humans. Investigators also are encouraged to use networks as an opportunity to generate pilot data in support of highly focused hypotheses. Research Themes and Questions The following is a listing of possible research questions for organizing networks. It is intended to be used only as a guide in formulating themes that could be used in developing networks. Are there systematic individual differences in HPA reactivity, and if so, what are their implications for behavior and psychopathology? How is vulnerability determined in the homeostatic processes associated with the HPA system? And, what determines resiliency and recovery of this system? How can study of the development of glucocorticoid expression and sensitivity in animal and primate brain further inform the understanding of development and psychopathology in humans? What is the nature (e.g., controllable vs. uncontrollable; physical vs. social stress) and timing (e.g., perinatal, 6 months, puberty) of environmental events that affect HPA regulation and development and that pose the greatest risk for psychopathology? What determines glucocorticoid sensitivity in brain cells, does this vary with development, and how does this affect behavior and psychopathology? In addition, networks can be developed to address combinations of questions. Examples of such questions include, but are not limited to the following: What other measures of internal state (e.g., metabolic, physiological) could be used to compliment measures of HPA regulation and health in humans? What are the environmental, behavioral, and neuronal mechanisms that down- regulate the HPA system and how does this regulation affect health? What interventions (both environmental and biological) can be developed to target HPA regulation and further test the role of HPA in psychopathology? How do changes in cognitive abilities associated with human development (e.g., cognitive development during puberty) affect HPA regulation? What animal models could be used to address these questions? What is the comparability of the HPA system across species, in terms of development and pathways of action? Are there differences between males and females in HPA function, and are corticolimbic interactions related to HPA function? What are the mechanisms of the diurnal output of the HPA system, and how does this relate to neural and behavioral development? How do changes associated with normal behavioral development correlate with developmental changes in HPA regulation and accompanying corticolimbic interactions? How does early exposure to increased cortisol (as in the treatment of childhood asthma) affect HPA regulation and behavior? What are the regulatory factors controlling glucocorticoid receptor gene expression? 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 policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-105.html INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html 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. LETTER OF INTENT Prospective applicants are asked to submit, by January 17, 1999, a letter of intent that includes a descriptive title of the proposed network, the name, address, and telephone number of the Principal Investigators participating in the proposed network, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 NIMH staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Della M. Hann, Ph.D. Division of Mental Disorders, Behavioral Research and AIDS National Institute of Mental Health 5600 Fishers Lane, Rm 18-105 Rockville, MD 20857 Telephone: (301) 443-9700 FAX: (301) 443-6000 Email: dhann@nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910; telephone (301) 435-0714; fax (301) 480-0525; Email: GrantsInfo@NIH.GOV. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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, (HPA Regulation: Cross-Disciplinary Research Networks, MH-99-003), must be typed in section 2 of the face page of the application form and the YES box must be marked. The R03 mechanism is limited to ten 10 pages for the substance of the application. Appendices including resumes and additional supporting information may be accepted, although the appendix may not be used to circumvent the page requirements. 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 must be sent to: Henry J. Haigler, Ph.D. Division of Extramural Activities National Institute of Mental Health 5600 Fishers Lane, Room 9C-04 Rockville, MD 20857 Applications must be received by February 17, 1999. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by NIMH staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. An appropriate peer review group convened by the NIMH in accordance with the review criteria stated below will evaluate applications that are complete and responsive to the RFA for scientific and technical merit. 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 will be discussed, assigned a priority score, and receive a second level review by the National Advisory Mental Health Council. Review Criteria o Scientific, technical, or medical significance and originality of the conceptual framework for the proposed network. o Appropriateness and adequacy of the network design and membership to carry out cross-disciplinary discussion. o Qualifications and research experience of the Principal Investigator and network members. o Feasibility of network participants successfully completing scheduled meetings and activities. o Appropriateness of the proposed budget and duration in relation to the proposed network goals. o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the network. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Scientific merit as determined by peer review and programmatic priorities will be the primary criteria for award determination. Only applications judged to have met the highest scientific standards of excellence will be considered for award. Networks must demonstrate feasibility for integrated discussions among investigators in pursuit of cross-disciplinary research agendas. Networks proposing themes, which address high-risk experimental questions, but high potential benefits, will be given careful consideration. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Della M. Hann, Ph.D. Division of Mental Disorders, Behavioral Research, and AIDS 5600 Fishers Lane, Rm 18-105 Rockville, MD 20857 Telephone: (301) 443-9700 FAX: (301) 443-6000 Email: dhann@nih.gov Israel Lederhendler, Ph.D. Division of Basic and Clinical Neuroscience Research National Institute of Mental Health 5600 Fishers Lane, Rm 11C-16 Rockville, MD 20857 Telephone: (301) 443-1576 FAX: (301) 443-4822 Email: ilu@helix.nih.gov Douglas L. Meinecke, Ph.D. Division of Basic and Clinical Neuroscience Research National Institute of Mental Health 5600 Fishers Lane, Rm 11C-06 Rockville, MD 20857 Telephone: (301) 443-5288 FAX: (301) 443-4822 Email: dmein@helix.nih.gov Direct inquiries regarding fiscal matters to: Diana S. Trunnell Grants Management Branch National Institute of Mental Health 5600 Fishers Lane, Room 7C-08 Rockville, MD 20857 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: Diana_Trunnell@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.242. Awards are made 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. Awards will be administered under PHS grants policy as stated in the NIH Grants Policy Statement (October 1, 1998). PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the nonuse 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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