Full Text MH-97-003 MOLECULAR APPROACHES TO MENTAL DISORDERS OF LATE LIFE NIH GUIDE, Volume 26, Number 13, April 25, 1997 RFA: MH-97-003 P.T. 34 Keywords: Mental Disorders Neuroscience Psychopathology National Institute of Mental Health Letter of Intent Receipt Date: June 5, 1997 Application Receipt Date: July 10, 1997 PURPOSE The principal objective of this Request for Applications (RFA) is to attract new investigators to build upon and extend basic research on fundamental aspects of neuronal function to develop clinical approaches to the understanding of mechanisms, clinical course, and treatment of late life mental disorders. The results of these investigations are expected to lead to the development of novel therapeutic strategies that reduce symptoms of psychopathology and improve neurobehavioral functioning in late life. The major focus of this RFA is on late onset mental disorders: psychoses, affective disorders, and anxiety disorders. 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), Molecular Approaches to Mental Disorders of Late Life, is related to the priority area of mental health and mental disorders. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for these awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) First Independent Research Support and Transition (FIRST) (R29) award and the small grant program (R03) award. The anticipated award date is September 30, 1997. Investigators seeking support for topics relevant to this RFA through other mechanisms such as career development awards (K series) or other research grant mechanisms (R01, R10, etc.) are encouraged to submit investigator-initiated applications using regular NIH procedures. 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. Because the small grants and FIRST awards have special eligibility requirements, application formats, and review criteria, applicants are strongly encouraged to consult with program staff listed under INQUIRIES and obtain the appropriate guidelines for these grant mechanisms. FUNDS AVAILABLE It is estimated that $750,000 (total costs) is available for support of up to 10 new awards. RESEARCH OBJECTIVES Background Dramatic advances have taken place in our understanding of the basic cellular and molecular biology of neuron function. Four areas of investigation have produced results that hold exceptional promise for application to the treatment of mental disorders of late life. These areas include: the molecular basis of signal transduction and its relation to neural plasticity and long term adaptation; neurotrophic growth factors and their effects on neural function and pathology; the mechanisms of programmed cell death in the aging brain; and the functional impact of cell death, growth factors, and signal transduction on patterns of neural connectivity and function. This RFA is intended to promote and facilitate the translation of these basic research findings into clinically applicable technologies. Major goals will be the elucidation of fundamental mechanisms of late life mental disorders with the intention of immediate or near-term development of novel therapeutic approaches. Clinical applications include depression, psychosis, and anxiety disorders of late life. As the molecular events associated with signal transduction are known in greater detail, it is increasingly appreciated that interactions between signaling molecules are a major determinant of how neurons respond to stimuli. Following activation of a receptor by its ligand, a cascade of biochemical events takes place. Changes in signal transduction systems are believed to form the basis for many phenomena associated with neural plasticity and adaptation to chronic stimuli. Thus chronic exposure to psychotropic drugs may lead to alterations in expression of G proteins, protein kinases, and many other signal transduction-associated molecules that alter the way neurons respond to synaptic transmitters. These chronic changes lead, in turn, to alterations in behavior, thought process, and affect. There is growing evidence that aging itself produces changes in signal transduction systems that alter neuronal function. The investigation of age-associated changes in signal transduction may lead to significant advances in our understanding of the mechanisms of mental disorders of late life and to the development of new treatment approaches. Molecular signaling processes often converge, overlap, and influence each other at many levels from receptors to transcription factors. Thus, a cell is constantly integrating signals from multiple neurotransmitters, growth factors, matrix and adhesion molecules, and hormones. This "crosstalk" between signaling systems may explain a wide variety of neurobiological phenomena ranging from LTP to cross-tolerance among addicting drugs. Crosstalk may also account for interactions that occur when combinations of psychotropic drugs are used to treat patients who have complex affective and psychotic symptoms or when augmentation strategies are employed to treat patients who are refractory to single agents. The aging process may produce alterations in patterns of crosstalk between signaling systems that result in significant functional changes in neurons. Interactions between growth factor-related signaling and neurotransmitter-associated systems is of special interest in understanding the effects of aging on central nervous system function. A major opportunity exists for the application of refined understanding of signal transduction mechanisms to the development of pharmacotherapeutics for late life mental disorders. In particular, the study of the effects of aging on signal transduction processes and neuronal plasticity will lead to new understanding of drug mechanisms and to the development of novel therapeutic strategies for mental disorders of late life. In addition, new augmentation strategies and drug combination protocols may be developed that exploit interactions between signaling systems. Moreover, signaling systems that are difficult to target with conventional pharmacotherapeutic agents such as growth factor or neuropeptide receptors may be influenced indirectly by activating or inhibiting distinct signaling pathways. Our knowledge of the mechanisms underlying destruction and degeneration of cell groups in the brain is rapidly advancing. Currently, there is substantial evidence that programmed cell death is a major mechanism underlying many neurodegenerative processes in the nervous system. Programmed cell death utilizes mechanisms and pathways that are common to many forms of injury including trauma, ischemia, infectious agents, and the aging processes. Neuronal cell death in specific brain regions is believed to be associated with the development of neuropsychiatric symptoms in late life. For example, degenerative changes of subcortical nuclei including the nucleus basalis of Meynert, the substantia nigra, the locus coeruleus, and the dorsal raphe may be associated with disorders of cognition, thought, affect, and anxiety in the elderly. In addition to neuronal cell death, mental disorders of aging may reflect dysregulation of growth factor activity leading to atrophic or dystrophic changes in neuron structure and function. Because of their role in preventing cell death, neurotrophic growth factors have been the subject of intense research as therapeutic agents in the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. In addition to blocking programmed cell death, neurotrophic growth factors are among the most potent modifiers of neuronal function known. Growth factors alter electrochemical activity, neurotransmitter synthesis and release, axonal transport, signal transduction, gene transcription, and cellular structure. Because of these properties, neurotrophic growth factors may be useful in the treatment of other mental disorders of aging that are believed to involve either atrophic or dystrophic changes in neurons. These disorders include late-onset psychoses, affective disorders, and anxiety disorders. Lastly, neurotrophic growth factors play a protective role in ischemic injury produced by stroke and microvascular disease. This suggests that growth factors may be useful in the treatment of vascular dementias, post-stroke depression, and other late life mental disorders associated with vascular insufficiency. In addition to growth factors, small molecules that influence growth factor signaling and apoptosis-related biochemical events are currently being developed and investigated. However, to facilitate this process, more research is needed into the basic mechanisms of cell death and growth factor action. In addition, research is needed to develop wider applications of neurotrophic and anti-apoptotic therapeutic strategies to diseases of the central nervous system. Neurotrophic growth factors and other drugs that exert trophic effects on neurons present an exceptional opportunity for investigation as novel therapeutic agents for mental disorders of late life. A central goal of this RFA is to stimulate the investigation of the mechanisms of action of neurotrophic growth factors and to explore potential therapeutic applications of growth factors and related agents to neuropsychiatric disorders of aging. Major opportunities for advancing the field exist in each of the following areas: 1) elucidation of basic biochemical mechanisms of programmed cell death and neurotrophic growth factor action; 2) application of growth factors to the treatment of neuropsychiatric disorders (including development of novel strategies for CNS delivery); 3) development of small molecules the mimic the effects of growth factors or modulate growth factor signaling; 4) exploration of other novel anti-apoptotic therapeutic agents. Neural cell death, atrophy, and other age-related changes profoundly alter patterns of connectivity and neural circuitry in the aging brain. In addition, neurotrophic growth factors have recently been shown to significantly influence connectivity. Moreover, biochemical changes in signal transduction mechanisms influence the functional and electrophysiological properties of neural circuits. Therefore, a pivotal step in the translation of molecular research into behavioral and clinical application is the investigation of neural connectivity in the aging brain. Rapid advances are being made in the study of neural circuitry and its relationship to behavior. A major area to be supported by this RFA focuses on investigation of molecular processes of aging at the level of neural connectivity emphasizing its implications for behavior and therapeutics. Research Issues Broad research objectives appropriate to this RFA include (but are not limited to) the following: Identification of changes in signal transduction systems that occur in normal aging and disease states Elucidation of the molecular mechanisms of enhanced receptor sensitivity following chronic dopaminergic receptor blockade Evaluation of the chronic effects of drug treatment and stress on signaling proteins in the aging brain Anatomical and electrophysiological studies of the effects of growth factors and chronic drug treatment on neural circuitry and behavior in the aging brain Investigation of interactions between signaling systems (e.g. growth factor-induced kinase activity that modulates neurotransmitter-associated signaling cascades)in the aging brain Investigation of changes in expression of neurotrophic growth factors, cytokines, growth factor-associated receptors and signaling molecules in the aging brain Identification of novel neurotrophic factors and cytokines expressed in the aging brain Investigation of the physiological role of growth factors and cytokines in the adult brain Investigation of non-neurotrophic effects of growth factors on neuronal functioning Elucidation of basic mechanisms of programmed cell death in the aging brain as it may relate to late life mental disorders Development and application of small molecules that influence (activate or inhibit) growth factor-related signaling and apoptotic cell death mechanisms such as tyrosine phosphatase inhibitors, ICE inhibitors, bcl-2-like molecules etc. Development of technology to improve delivery of growth factors and other large molecular ligands across the blood brain barrier Studies of neurobehavioral effects of neurotrophic growth factors and cytokines in the aging brain Application of antisense technology to modulate expression of key signaling, neurotrophin-related, or apoptosis-associated gene to determine effects of such procedures on behavior Development of clinical imaging technology to assess signal transduction systems in the aging brain Development of clinical pharmacological challenge protocols that assess signal transduction and trophic states in the aging brain INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by June 5, 1997, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, 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: Herbert W. Harris, M.D., Ph.D. Division of Clinical and Treatment Research National Institute of Mental Health Parklawn Building, Room 18-101 Rockville, MD 20857 Telephone: (301) 443-1185 FAX: (301) 574-6784 E-mail: hharris@ngmsmtp.nimh.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910; telephone (301) 710-0267; fax (301) 480-0525; Email: ASKNIH@ODROCKM1.OD.NIH.GOV. Applications for the FIRST award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The RFA label available in the PHS 398 (rev. 5/95) 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, MH-97-003, Molecular Approaches to Mental Disorders of Late Life, must be typed in section 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/overnight mail service) At the time of submission, two additional copies of the application must be sent to: Henry J. Haigler, Sr., Ph.D. Division of Extramural Activities National Institute of Mental Health Parklawn Building, Room 9C-08 Rockville, MD 20857 Telephone: (301) 443-1340 Fax: (301) 594-0702 Email: hhaigler@nih.gov Applications must be received by July 10, 1997. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG 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 NIH Division of Research Grants (DRG) and for responsiveness by NIMH staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 NIMH in accordance with the review criteria stated below. 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 appropriate national advisory council or board, when applicable. Review Criteria o ability of investigators to engage a multi disciplinary research program spanning basic to clinical research with the endpoint of enhancing our understanding of mental disorders of late life o Focus of the investigation on the specific mental disorders of aging which include: major mood disorders, anxiety disorders, psychotic (thought) disorders with a lesser focus on Alzheimer's disease o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. AWARD CRITERIA Award criteria are: scientific merit as determined by peer review, availability of funds, and programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Herbert W. Harris, M.D., Ph.D. Mental Disorders of the Aging Research Branch Division of Clinical and Treatment Research National Institute of Mental Health Parklawn Building, Room 18-101 Rockville, MD 20857 Telephone: (301) 443-1185 FAX: (301) 574-6784 E-mail hharris@helix.nih.gov Direct inquiries regarding fiscal matters to: Diana S. Trunnell Assistant Chief, Grants Management Branch National Institute of Mental Health Parklawn Building, 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 Public Health Service Grants Policy Statement (April 1, 1994). 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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