Full Text MH-97-001 INNOVATIVE APPROACHES FOR MICROSCOPIC TRACT-TRACING NIH GUIDE, Volume 26, Number 2, January 17, 1997 RFA: MH-97-001 P.T. 34 Keywords: Nervous System Electron Microscopy Biological Resources Disease Model National Institute of Mental Health National Institute on Aging Letter of Intent Receipt Date: April 15, 1997 Application Receipt Date: June 11, 1997 PURPOSE The National Institute of Mental Health (NIMH) and the National Institute on Aging (NIA) invite applications for grant support to research and develop innovative tract-tracing approaches to study the connectivity of the nervous system at the level of the light and/or electron microscope. Particularly encouraged are applications which propose research and development of novel tract-tracing techniques to be used in post-mortem human and animal tissue, especially aldehyde-fixed tissue. All applications proposing research on innovative tract-tracing approaches will, however, be considered pertinent to this Request for Applications (RFA). This RFA is issued in response to the need for better ways to demonstrate neural connections in humans and in nonhuman animal models. Research and development of novel methods and/or reagents to clearly, reproducibly, and rapidly trace distant connections at the level of the light and/or electron microscope in post-mortem tissue would represent a major advance in the understanding of normal and pathological brain organization. Among the opportunities that this would make available would be direct comparisons of the detailed connectivity of circuits that underlie important mental functions across normal animals, aged animals, animal models of disease, non-diseased humans and humans with mental disorders and age-related nervous system disorders. Moreover, the ability to trace connections in aldehyde-fixed tissue would allow such methods to be used in conjunction with a variety of other methods currently used to study the microstructure of the brain. 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 RFA, Innovative Approaches for Microscopic Tract-Tracing, is related to the priority areas of mental health, mental disorders, and age-related brain 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 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. Foreign institutions are not eligible for small grants (R03) from the NIMH (for additional eligibility requirements for NIMH small grants, see PAR-97-015, NIH Guide for Grants and Contracts, Vol. 25, No. 4, December 6, 1996). MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and small grant (R03). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an R01 grant application submitted in response to this RFA may not exceed four years. An R03 grant application submitted in response to this RFA, may request up to $50,000 per year (direct costs) for up to two years and may include salary support for the principal investigator. The anticipated award date is September 1997. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will vary also. This RFA is a 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 grant has special eligibility requirements, application formats, and review criteria, applicants are strongly encouraged to consult with program staff listed under INQUIRIES and obtain the appropriate additional announcements for that grant mechanism. FUNDS AVAILABLE It is estimated that approximately $1,000,000 will be available for research projects (R01) and small grants (R03) funded under this RFA. It is expected that this will support eight to twelve such awards, depending upon the mix of mechanisms. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Although the financial plans of NIMH and NIA include these proposed levels of support, awards made under this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Neural circuits form the neural substrate of the complex information processing carried out in the brain in both health and illness. Not only does the function of the central nervous system depend upon the connections that are made by its constituent neurons, but the function of any given region of the brain depends upon the particular connections that region has with other regions of the nervous system. This tenet holds from the level of groups of neurons, such as a cortical area or subcortical nucleus, all the way down to the level of the individual neuron and even to the subcellular level. Not surprisingly, much of contemporary understanding of brain function, as well as the formulation of new hypotheses, is based on knowledge regarding specific connections of particular brain regions or neurons. In the last 20 years, the development and use of a variety of tracer substances (e.g., tritiated amino acids, horseradish peroxidase, fluorescent dyes, dextrans, and biocytin), approaches (e.g., histochemistry, immunolabeling, fluorescence microscopy, and autoradiography) and reagents (e.g., diaminobenzidene and tetramethylbenzidene) have produced explosions of new data and insights. Most tract-tracing approaches, however, require the deposit of tract-tracing substances in vivo, and depend on axoplasmic flow for their transport. This mechanism renders difficult the use of such methods in some areas of animal research, such as study of brain connectivity early in development, and, of course, precludes their use in humans. There are very few tract-tracing approaches that can be applied to post-mortem tissue, and these approaches have severe limitations such as being capricious, extremely slow, or being able to demonstrate connections only over very small distances. Thus, despite the wealth of knowledge that has accumulated regarding neural connectivity in a variety of species, very little is known about the detailed connections of the human brain. The ability to demonstrate detailed distant neural connections in human post-mortem tissue would permit direct comparison of the normal connectional organization of the human brain with the vast literature on neural connections obtained in animal models and would allow a more critical evaluation of the relationship of animal models of brain disorders to human disease. Obversely, this capacity would also reveal the alterations of neural circuits associated with specific pathologies, such as Alzheimer's Disease and other neurodegenerative diseases, and would facilitate the development of better animal models of these pathologies. This technique could also delineate changes in neural circuits, including axonal degeneration, which are seen in normal and pathological aging. Since it is likely that approaches capable of demonstrating neural connections in human pos-mortem tissue would also work in non-human post-mortem tissue, these tools would represent important additions to the arsenal of techniques available to study connections in nonhuman species. Experimental approaches and disciplinary perspectives brought to bear on research proposed by applicants are unrestricted and may be multidisciplinary or interdisciplinary. The following are examples of some of the research topics that would be relevant to this RFA: o identification and evaluation of molecules which rapidly diffuse through lipids fixed in aldehydes, such as those aldehydes used to fix human tissue; o development of procedures to visualize tract-tracing molecules in aldehyde-fixed tissue; o evaluation of efficacy of novel tract-tracing methods across different neural systems, across different species, and across different ages; o studies of parameters limiting the uptake and/or movement of novel agents along axons and diffusion between neural cells; o assessment of novel tract-tracing molecules to identify local neural circuits as well as long distance neural connections; o structure-function models to predict the efficacy of specified molecules to demonstrate connections in post-mortem timmue; o evaluation of the ability of novel tract-tracing molecules to identify degenerating or dysfunctional axons in animal models of neuronal degeneration; o evaluation of the compatibility of novel tract-tracing methods with other commonly used methods of microstructural analysis, such as immunolabeling or histochemical staining; o development of procedures to co-visualize novel tract-tracing molecules with cell-specific markers in order to identify specific neuronal populations and their connections. These broad objectives are meant to be illustrative and are not exclusive of other objectives appropriate to this RFA. Since the purpose of this RFA is to stimulate research and development of new tract-tracing approaches, an important aspect of the proposed efforts is the manner in which these new approaches will be evaluated and compared to existing approaches. This evaluation should be scientifically valid, objective, and as quantitative as possible. Scientific interaction among principal investigators supported as a result of this RFA is encouraged. 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 April 15, 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 and NIA staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Michael F. Huerta, Ph.D. Division of Neuroscience and Behavioral Science National Institute of Mental Health Parklawn Building, Room 11-103 Rockville, MD 20857 Telephone: (301) 443-3563 FAX: (301) 443-1731 Email: mhuerta@helix.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 Division 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. Guidelines for NIMH small grants (R03) are available on the NIMH home page (www.nimh.nih.gov) under research grants (PAR-97-015), the NIMH FAX4U (301-443-4513), and or may be obtained from the NIMH program director listed under INQUIRIES. 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-97-001; Innovative Approaches for Microscopic Tract-Tracing", 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@ngmsmtp.nimh.nih.gov Applications must be received by June 11, 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 DRG and for responsiveness by NIMH and NIA 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 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 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 likelihood that the work will advance the ability to demonstrate neural connectivity; o appropriateness and adequacy of plans to evaluate tract-tracing approaches developed under this RFA; 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 o potential to advance the field; o scientific merit of the proposed research as determined by peer review; o responsiveness to the purposes and objectives outlined in this RFA; o availability of research funds; o 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: Michael F. Huerta, Ph.D. Division of Neuroscience and Behavioral Science National Institute of Mental Health Parklawn Building, Room 11-103 Rockville, MD 20857 Telephone: (301) 443-3563 FAX: (301) 443-1731 Email: mhuerta@helix.nih.gov Bradley C. Wise, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3C30 - MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: wiseb@gw.nia.nih.gov Direct inquiries regarding fiscal matters to: Diana S. Trunnell 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 Joseph Ellis Grants Management Officer National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212 - MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: ellisj@gw.nia.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.242 (NIMH) and 93.866 (NIA). 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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