XENOBIOTICS AND CELL DEATH/INJURY IN NEURODEGENERATIVE DISEASE Release Date: January 29, 1999 PA NUMBER: PAS-99-054 P.T. National Institute of Environmental Health Sciences National Institute on Aging National Institute of Neurological Diseases and Stroke National Institute of Mental Health PURPOSE The objective of this Program Announcement (PA) is to stimulate research on the relative roles of environmental, endogenous neurochemical and genetic factors in the cause of neurodegenerative diseases. The results of these investigations should help clarify the part xenobiotics play in the etiology 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, Xenobiotics and Cell Death/Injury in Neurodegenerative Disease, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html. 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. FUNDS AVAILABLE The total estimated funds available for support of this Program Announcement is $2,000,000 per year. This level of expenditure is dependent on the type of applications received and the high scientific quality of those applications. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed 5 years. RESEARCH OBJECTIVES Much of the previous research in neurodegenerative diseases and dysfunction has focused on the underlying biological processes critical to disease manifestation in the hopes of developing new treatments, however, the relative roles of environmental, endogenous neurochemical and genetic factors in the cause of neurodegenerative diseases remain unclear. Several studies have implicated these factors in Parkinson"s disease (PD), Alzheimer"s disease (AD), and amyotrophic lateral sclerosis (ALS). For example, it is not understood whether differences in prevalence rates of Parkinson"s disease in various communities may be due to the differential distribution of a hypothetical environmental toxicant or may be more frequent where a heritable defect is more common. Moreover, analytic epidemiological studies have varied in case and control selection methodology and venues (e.g., clinics, population bases, different countries) partly accounting for the disparate conclusions reached by investigators. Attempts are needed to understand the contribution of environmental exposure, endogenous susceptibility factors, and increasing age in the etiopathology of neurodegenerative disease and will require a concurrent advancement and refinement of methodologies and sciences. Of particular significance may be those approaches that can be used across species from lower animals to humans. Such approaches permit a precise characterization in animal models of alterations arising from defined environmental exposures which can serve as a cogent guide to underlying cellular and molecular mechanisms. This program announcement is issued to encourage and foster investigator- initiated basic and applied research on the possible role of xenobiotics in brain cell death and injury resulting in neurodegenerative diseases. Consequently, the participating Institutes are interested in supporting research in (but not limited to) the following areas: Development of biomarkers of preclinical disease to identify those at risk for selected environmental toxicants, and to identify those who would benefit from trials of possibly neuroprotective drugs. Development of criteria to standardize techniques for the early diagnosis of disease to enhance the reliability of clinical and epidemiological studies. Development of clinical imaging technology to enhance diagnosis and examine the efficacy of therapeutic intervention. Epidemiological studies aimed at identifying specific agents and/or combination of chemicals associated with an increased risk for neurodegenerative disorders. These studies may target populations already characterized in terms of the incidence and risks for neurodegenerative diseases (e.g., farmers with significant exposure to pesticides). Development of models of low-level and/or chronic exposure to environmental agents and synergistic chemical interactions leading to neuronal injury. These paradigms are more likely to reflect the pattern of exposure(s) and development of neurodegeneration. Studies using genetically modified, transgenics, and knockout animals to study increased susceptibility to environmentally induced neurodegeneration and the efficacy of therapeutic interventions. Development of models (including toxicant-induced paradigms) for studying the mechanism of formation and the role of Lewy body and Lewy body-like inclusions (PD) as well as amyloid plaques (AD) in neurodegeneration. Studies on the effect of aging on toxicant-induced neurodegeneration, since aging is a risk factor for a number of neurodegenerative diseases. Studies on the role of inflammatory processes in toxicant-induced neurodegeneration. Inflammation may be the process by which an acute exposure to toxic agents could lead to chronic neurodegeneration. Studies on neuronally-derived proteins such as -synuclein (PD) and presenilin (AD) and their potential roles in toxicant-induced neurodegeneration. Studies examining xenobiotics" potential influence on programmed cell death, neural plasticity, or other processes critical to the maintenance of neuronal viability and function. Studies on remediation of neuronal defects using strategies such as gene therapy. Applications that are collaborations between basic and clinical neuroscientists and/or interdisciplinary in nature are encouraged. Also, the National Institute on Mental Health (NIMH) has particular interest in studies in the following areas: using genetically modified, transgenics, and knockout animals as models of behavioral traits or phenotypes relevant to mental disorders, and the development and validation of biomarkers and clinical imaging technologies to enhance diagnosis, disease progression, and efficacy of therapeutic intervention in mental disorders. 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 have been 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 the following URL address: http://www.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://www.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained 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, email: GrantsInfo@nih.gov. They may also be downloaded from the internet at http://www.nih.gov/grants/forms.htm. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. The applicant must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://www.nih.gov/grants/guide/notice-files/not98-030.html. The title and number of the program announcement 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 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) REVIEW CONSIDERATIONS Applications 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 will evaluate applications 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, 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 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 the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the 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, an investigator 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 this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? 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? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The reasonableness of the proposed budget and duration in relation to the proposed research. 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. The initial review group will also examine the provisions for the protection of human subjects and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications. 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 are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Annette G. Kirshner, Ph.D. Division of Extramural Research and Training National Institute of Environmental Health Science Box 12233, MD EC-23 Research Triangle Park, NC 27709 Telephone: (919) 541-0488 FAX: (919) 541-5064 Email: kirshner@niehs.nih.gov Eugene J. Oliver, Ph.D. Division of Stroke, Trauma and Neurodegenerative Disorders National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 806 Bethesda, MD 20892 Telephone: (301) 496-5680 FAX: (301) 480-1080 Email: eo11c@nih.gov Bradley Wise, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3C307, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: wiseb@exmur.nia.nih.gov Linda Brady, Ph.D. Preclinical and Clinical Therapeutics Research Branch National Institute of Mental Health 5600 Fishers Lane, Room 11-97 Rockville, MD 20857 Telephone: (301) 443-9875 FAX: (301) 443-4822 Email: lb@helix.nih.gov Direct inquiries regarding fiscal matters to: Mr. David Mineo Division of Extramural Research and Training National Institute of Environmental Health Science Box 12233, MD EC-22 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 FAX: (919) 541-2860 Email: mineo@niehs.nih.gov Pat Driscoll Grants Management Branch National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 1004 Bethesda, MD 20892-9190 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: pd23n@nih.gov Joseph Ellis Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 3C307, MSC 9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: joseph_ellis@nih.gov 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. 93.113, 93.866 93.854, 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. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and 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, and 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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices



NIH Office of Extramural Research Logo
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy
NIH... Turning Discovery Into Health®



Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.