Full Text PA-96-058 MECHANISM OF CELL DEATH AND INJURY IN NEURODEGENERATIVE DISORDERS NIH GUIDE, Volume 25, Number 19, June 14, 1996 PA NUMBER: PA-96-058 P.T. 34 Keywords: Neuroscience Biology, Cellular Injury Aging/Gerontology Genetics National Institute of Neurological Disorders and Stroke National Institute on Aging National Institute of Environmental Health Sciences National Institute of Mental Health PURPOSE The principal objective of this Program Announcement (PA) is to stimulate research on the basic mechanisms of neuronal cell death and injury as they relate to neurodegenerative disorders. The results of these investigations are expected to help in elucidating the pathogenesis of these diseases. 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 PA, Mechanism of Cell Death and Injury in Neurodegenerative Disorders, is related to the priority area of chronic debilitating diseases. 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 and foreign, 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 program project (P01) grants or First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The mechanisms available for support of this PA are the National Institutes of Health (NIH) research project (R01), program project (P01), and FIRST (R29) award. Responsibility for the planning, direction, and execution of the proposed research project will be solely that of the applicant. Because the nature and scope of the research proposed in response to this PA may vary, it is anticipated that the size of an award will also vary. RESEARCH OBJECTIVES Background An important theme in current neuroscience is the search for common mechanisms underlying the destruction of particular cell groups that are unique to individual neurodegenerative disorders. The study of one disorder frequently yields information about the others. There is much accumulating evidence that the regulation of programmed cell death in the nervous system utilizes mechanisms and pathways which are common to simple and complex organisms, to pathways expressed in normal development, to responses to many modes of injury such as trauma, ischemia, and environmental and biological agents, to diseases of early and adult life, and to aging processes. Further progress depends on a broad-based research effort uniting basic and clinical studies over a broad range of approaches. Studies of the interaction between environmental, metabolic, anatomical, and genetic factors are important research directions. Using newly developed technologies, scientists from diverse fields and disciplines are in a position to make significant progress in understanding the critical issues raised by the neurodegenerative disorders and the mechanisms of the selective vulnerability of cells of the central nervous system. Although the pathway of cell death may be common, these disorders are associated with a variety of risk factors including genetic and environmental events. For example, familial amyotrophic lateral sclerosis (FALS), familial Alzheimer's disease (FAD), and Huntington's disease (HD) are autosomal dominant, age related, genetic disorders. Familial Parkinson's disease (PD) has been reported in a few large possibly autosomal dominant Parkinson's disease pedigrees. Still, except for HD, most cases of these disorders have not been shown to be of genetic origin. Exogenous agents including neuroleptic drugs used in the treatment of schizophrenia can cause tardive dyskinesia with PD-like symptoms. While the etiology of many neurodegenerative disorders is unknown, the mechanisms by which the neurons die may be similar. Neurodegenerative diseases occur when a significant proportion of neurons die. The cause of the selective vulnerability of these cells is not known. Implicated in this destruction as well as in destruction of neurons following neuronal injury are oxidative stress by free radical damage, defective energy metabolism, external or internal toxins, genetic factors, and aging. Altered regulation of programmed cell death during development may be involved in the etiology of specific mental disorders. Alone or in combination, these factors could lead to necrotic or apoptotic cell death. Changes in mitochondrial function with age or injury can alter cellular energetics, free radical metabolism, and vulnerability to further harm. Defects in energy metabolism at the mitochondrial level may contribute to activation of excitatory amino acid receptors which may then lead to calcium influx. Defects in energy metabolism further impair intracellular calcium buffering. A consequence of increasing intracellular calcium is cell damage and death. It is also quite possible that oxidative stress itself may lead to damaged mitochondrial DNA with subsequent further deterioration of respiratory enzyme activities. Previous work has demonstrated that the MPTP toxicity, which mimics Parkinson's disease, involves inhibition of complex 1 of the electron transport chain as well as oxidative stress. It has also been recently demonstrated that the generation of nitric oxide appears to play a role in cell death in the MPTP animal model. Research is needed to develop and use novel cell culture techniques and transgenic animal models to study the possible role of defective organelles and aberrant metabolism in the pathophysiology of these disorders. Modern imaging techniques such as functional magnetic resonance spectroscopy may be valuable in studying alterations in metabolism caused by neuronal injury or degeneration. Also, the development of biochemical markers of oxidative stress in cerebrospinal fluid, plasma and urine will help to assess directly whether or not oxidative damage is a significant factor in these disorders. Metals are implicated in the etiology of a number of neurodegenerative disorders. Wilson's disease, for example, is a systemic genetic disorder of copper metabolism and Hallervorden-Spatz disease is characterized by deposits of melanin pigment containing calcium and iron. Studies of disease where metals play a role in their pathogenesis may shed light on basic mechanisms leading to cell destruction and death. Applications describing studies involving the role of metals in various neurodegenerative disorders will be considered responsive to this PA. Neuronal apoptosis is a stereotypical pattern of changes associated with cell death in response to a variety of insults. Major themes in apoptosis research involve the critical regulators of terminal apoptosis. Those most clearly associated with this terminal process are the pro-apoptotic and anti-apoptotic members of the bcl-2 family, and the family of ICE-like cystine proteases that appear to be required. Much of what we know of these mechanisms is derived from studies of simple organisms such as C. elegans and Drosophila and further work in such systems is recognized as relevant to knowledge of more complex organisms and thus responsive to this PA. Work is needed to define patterns of expression of these gene families in neurons, the determinants of those expression patterns, the molecular mechanism(s) by which they regulate apoptosis, and ultimately the development of strategies to mimic the anti-apoptotic and inhibit the pro-apoptotic activity of the gene products. Several pertubations of neurons lead ultimately to apoptosis. Some of these require ongoing protein synthesis to lead to apoptosis, whereas others do not. Effort is needed to understand the genetic and biochemical alterations that lead a cell ultimately to apoptosis in response to various insults and pathologic processes. Examples that require such study are growth factor deprivation, oxidation stress, and cellular toxins such as beta-amyloid. These studies need to provide, in addition to a description of alterations associated with death, the use of strategies to determine the importance of such alterations in the ultimate death of the cell. Study is required to determine the range of trophic factors that act on particular types of neurons, the physiological role of these factors in the cells in the developing and adult animal, and the pharmacological potential of the factors to both prevent death of the cells and to maintain their function. It is important to determine the signal transduction pathways by which trophic factors block cell death and enhance cell growth. It will be important to develop drugs which mimic or stimulate these pathways. The purpose of this PA would be to increase existing knowledge by stimulating research to investigate further the mechanisms of neuronal cell death and injury as they may contribute to our understanding of neurodegenerative disorders. Related situations such as cell death in development or response to diverse injury are regarded as relevant and responsive. As discussed above, important areas of investigation would be on the roles of energy impairment, excitotoxicity, oxidation stress, nitric oxide, metals, and calcium in either apoptotic or necrotic cell death. Research focused on normal and pathological neuronal apoptotic mechanisms including genetic and biochemical alterations resulting from injury or pathological processes is clearly relevant. These areas, however, are not intended to be comprehensive or exclusionary. The investigation of potential therapeutic approaches targeted at rescuing or slowing the decline of the injured or degenerating neurons is also warranted. Researchers responding to this PA are encouraged to consider novel approaches of the broadest nature in approaching the pathogenesis of these diseases. 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 sub populations 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) and supersedes and strengthens the previous policies (concerning the inclusion of women in study population, and concerning the inclusion of minorities in study populations), which have been in effect since 1990. The current 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 INQUIRES. Program staff may also provide additional relevant information concerning the policy. 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 Institute 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. FIRST (R29) award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST award applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. In addition, the PA title and number (Mechanism of Cell Death and Injury in Neurodegenerative Disorders PA-96-053) must be typed on line 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/express service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. 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, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria 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 subjects and the safety of the research environment. AWARD CRITERIA The following criteria will be considered in making a funding decision: Applications will compete for available funds with all other approved applications assigned to these Institutes. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Eugene J. Oliver, Ph.D. Division of Demyelinating, Atrophic, and Dementing Disorders National Institute of Neurological Disorders and Stroke Federal Building, Room 806 7550 Wisconsin Avenue Bethesda, MD 20892-9150 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: eo11c@nih.gov Annette Kirshner, Ph.D. Division of Extramural Research and Training National Institute of Environmental Health Sciences Building 3, P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-0488 FAX: (919) 541-2843 Email: kirshner@niehs.nih.gov Neil Buckholtz, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Room 3C307 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: Bckholn@gw.nia.nih.gov Douglas L. Meinecke, Ph.D. Division of Neuroscience and Behavioral Science 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: Ms. Pat Driscoll Division of Extramural Activities National Institute of Neurological Disorders and Stroke Federal Building, Room 1004 7550 Wisconsin Avenue Bethesda, MD 20892-9190 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: driscolp@nswide.ninds.nih.gov Mr. David Mineo Grants Management Branch National Institute of Environmental Health Sciences Building 2, P. O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-7628 FAX: (919) 541-2860 Email: mineo@niehs.nih.gov Ms. Crystal Ferguson Grants Management Office National Institute on Aging Gateway Building, Room 2N212 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: fergusonc@gw.nia.nih.gov Ms. Diana Trunnell Grants Management Branch National Institute of Mental Health 5600 Fishers Lane, Room 7C08 Rockville, MD 20857 Telephone: (301) 443-3065 FAX: (301) 443-6885 Email: Diana_Trunnell@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.242 for Mental Health Research Grants, 93.853 and 93.854 for Neurological Disorders Grants, 93.113 for Environmental Health Grants, and 93.866 for Aging grants. 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. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and to promote the non-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. .
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