EFFECTS OF HYPOGLYCEMIA ON NEURONAL AND GLIAL CELL FUNCTION Release Date: August 7, 2001 RFA: RFA-NS-02-008 National Institute of Neurological Disorders and Stroke (NINDS, http://www.ninds.nih.gov/) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, http://www.niddk.nih.gov/) Juvenile Diabetes Research Foundation (http://www.jdrf.org) Letter of Intent Receipt Date: February 15, 2002 Application Receipt Date: March 15, 2002 THIS RFA USES THE MODULAR GRANT AND JUST-IN-TIME CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THS RFA. PURPOSE The National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Juvenile Diabetes Research Foundation (JDRF) solicit applications for studies designed to elucidate the effects of acute and recurrent episodes of hypoglycemia on glial and neuronal cells of the developing and mature central nervous system. Recent therapeutic strategies aimed at closely controlling elevated glucose levels in diabetic individuals put them at risk for experiencing episodes of hypoglycemia. Acute and recurrent hypoglycemia may cause transient or persistent alteration of cognitive function, and can result in seizures or coma. Recent studies of ischemia have provided information about the effects of glucose deprivation coupled with hypoxia on cells of the central nervous system. However, less is known about the effects of reduced glycemic levels on CNS cell function and survival in a normoxic environment. This RFA solicits basic studies 1) to define the effect of varying glycemic levels on cerebral metabolism, transport of glucose across the blood brain barrier, and astrocytic regulation of substrates for neuronal metabolism, and 2) to determine pathological consequences of acute and recurrent hypoglycemic insult on cells of the central nervous system. Two related RFAs solicit basic and clinical research specifically addressing the problems of hypoglycemia unawareness (DK-01-031) and prevention of hypoglycemia in patients with diabetes (DK-01-032). In addition, although not formally participating in this RFA, the National Institute on Aging is interested in research on the effects of hypoglycemia on neuronal and glial cell function in the aging nervous system. RESEARCH OBJECTIVES Background: Large-scale clinical trials have established the importance of intensified diabetes control in reducing the complications that result from poorly controlled hyperglycemic levels. However, therapeutic efforts to closely regulate glycemic levels may occasionally cause inadvertent and recurrent episodes of severe hypoglycemia. Acute hypoglycemic episodes may result in transient or persistent alteration of brain function. When plasma glucose levels fall below 3 mmol/L, cortical function deteriorates, confusion, abnormal behavior, seizures and coma can result. The effects of acute or recurrent episodes of hypoglycemia on the cells of the central nervous system are potentially harmful, and may impose long-lasting damaging effects on the brain. This is of particular concern in the early childhood years when the nervous system is still developing and in fetuses exposed to maternal hypoglycemia. The regulation of cerebral metabolism in settings of altered glycemia is poorly understood. It is recognized that astrocytes can provide fuel substrates to neurons, and that the glial cells contain glycogen. However, the regulation of glial intracellular glycogen and patterns of glycogen breakdown in settings of varied glycemic states is unknown. In the context of altered glycemic levels, alternative fuel sources supplied by astrocytes could ameliorate the effects of hypoglycemia on other cells of the central nervous system. However, recurrent hypoglycemic insults could potentially affect the ability of astrocytes to provide alternative fuel substrates, and this is an area that warrants investigation. In addition, the regulation of endothelial cell expression of glucose transporters may change in response to varied glycemic levels. There is substantial evidence that hypoglycemia alters human behavior, and recurrent episodes of severe hypoglycemia may lead to memory loss or impaired cognitive function. The pathogenesis of hypoglycemic- induced nerve cell injury is largely unknown, but mechanisms that could result in damage to cells of the CNS include, but are not limited to, excitotoxicity related to a dysregulation of the glutamate-glutamine cycle or an impaired capacity of astrocytes to generate reducing equivalents in the presence of oxidative stress. To understand the effects of acute or recurrent hypoglycemia on the cells of the central nervous system, it is essential to characterize the response of CNS cells to reduced glycemic levels, to determine the extent of CNS cell injury induced by hypoglycemia, and to identify the mechanisms involved in hypogylcemia-induced cell or tissue damage in brain. To highlight the problem of hypoglycemia in individuals with diabetes, the JDRF, NIDDK, NINDS, National Institute of Child Health and Development (NICHD), and NASA cosponsored a workshop on Hypoglycemia and the Brain on Sept. 7-8, 2000. Participants in the workshop identified a number of knowledge gaps requiring future research (http://www.jdf.org/research/workshop090800.pdf). Research is needed to enhance understanding of the effects of hypoglycemia on neuronal and glial cell metabolism and hypoglycemia-induced CNS cell injury. As a first step towards addressing this problem, the NINDS, NIDDK and JDRF have issued this RFA. Areas of interest This RFA solicits basic studies 1) to define the effect of varying glycemic levels on cerebral metabolism, transport of glucose across the blood brain barrier, and astrocytic regulation of substrates for neuronal metabolism, and 2) to determine the pathological consequences of acute and recurrent hypoglycemic insult on cells of the central nervous system. While an ischemic insult in the CNS subjects neurons and glia to glucose deprivation coupled with hypoxia, a hypoglycemic insult exposes the cells of the CNS to glucose deprivation in a normally oxygenated environment. The state of tissue oxygenation directly impacts the ability of cells to maintain glycolysis. Thus, this RFA seeks to solicit studies aimed at examining the effects of glucose reduction, which is physiologically relevant under normoxic conditions. Two related RFAs solicit basic and clinical research specifically addressing the problems of hypoglycemia unawareness (DK-01-031) and prevention of hypoglycemia in patients with diabetes (DK-01-032). Appropriate topics for investigation under this RFA would include but are not limited to: o Studies to determine the short and long-term effects of varying glycemic levels on glucose transport in the brain and how specific transporters may affect brain glucose metabolism o Studies to evaluate the role of glial-derived alternative fuels in the maintenance of neuronal and glial function o Studies to examine cellular physiological alterations in response to hypoglycemia o Studies to determine the role of astrocytic glycogen in maintaining neuronal function and survival during hypoglycemia o Studies to elucidate the effects of hypoglycemia on mechanisms regulating astrocytic uptake of glutamate o Studies to assess the extent and mechanism of CNS damage during acute or recurrent hypoglycemia, and to determine whether sensitivity to hypoglycemia varies with age (including in utero exposure) o Studies on the relationship between the astrocyte pentose phosphate pathway, oxidative stress, and brain injury during glucose deprivation o Studies on interactions between astrocytes and other cell types such as oligodendrocytes and their relationship to brain injury during hypoglycemia o Studies to determine whether there is a therapeutic window during which hypoglycemia-induced CNS damage can be ameliorated or reversed o Studies of potential agents (e.g. apoptosis inhibitors) that could be used to mitigate hypoglycemia-induced neuronal damage SPECIAL REQUIREMENTS Letter of Authorization Applicants should submit a brief letter to the NINDS indicating whether or not they wish their application to be considered for funding by the JDRF. While applicants may request that their applications be considered only by the NIH and not by the JDRF, it is necessary that the record indicate the applicant"s consideration of this opportunity. For those applicants who wish to have the JDRF consider their application, all materials relating to the application will be promptly forwarded to that organization and the summary statements for such applications will be shared with the JDRF when available. This separate letter may be submitted with the Letter of Intent (see below) or as a cover letter with the application. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research project grant (R01) award mechanism and the Exploratory/Development (R21) mechanism. The R21 awards are to demonstrate feasibility and to obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. These grants are intended to 1) provide initial support for new investigators, 2) allow exploration of possible innovative new directions for established investigators, and 3) stimulate investigators from other areas to lend their expertise to research within the scope of this solicitation. Applicants for the R21 must limit their requests to $125,000 direct costs per year and are limited to two years. These R21 grants will not be renewable, continuation of projects developed under this program will be through the regular research grant (R01) program. 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 application submitted in response to this RFA must not exceed four years and no more than $250,000 direct costs/year. 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. The anticipated award date is September 30, 2002. FUNDS AVAILABLE The NINDS and NIDDK intend to commit approximately $1,250,000 in FY 2002 to fund four to five new grants in response to this RFA. The JDRF intends to commit up to $250,000 in additional funds to co-fund research project grants that are both scientifically meritorious and fit within the mission and research emphasis areas of the JDRF. (See http://www.jdfcure.org, for more information.). All awards will be issued by the NINDS and the NIDDK. An applicant may request a project period of up to four years and a budget for direct costs of up to $250,000 per year (2 years and $125,000 for R21 s). Because the nature and scope of the research proposed might vary, it is anticipated that the size of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Toby Behar, Ph.D. Neural Environment Cluster National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Room 2114A Bethesda, MD 20892-9521 Telephone: (301) 496-1431 FAX: (301) 480-2424 Email: tb72Z@nih.gov Barbara Linder, M.D, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases NIDDK 6707 Democracy Boulevard, Rm. 699 MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-0021 FAX: (301) 480-3503 E-mail: linderb@extra.niddk.nih.gov Direct inquiries regarding review issues to: Lillian Pubols, Ph.D. Chief, Scientific Review Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Room 3208 Bethesda, MD 20892 Telephone: (301) 496-9223 FAX: (301) 402-0182 Email: lp28e@nih.gov Direct inquiries regarding fiscal matters to: Mary Graham Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Room 3258 Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: grahamm@ninds.nih.gov LETTER OF INTENT Prospective applicants are asked to submit 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 IC staff to estimate the potential review workload and plan the review. Prospective applicants are asked to submit, by February 15, 2002, a letter of Intent to be sent to: Toby Behar, Ph.D. Neural Environment National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Room 2114A Bethesda, MD 20892-9521 Telephone: (301) 496-1431 FAX: (301) 480-2424 Email: tb72Z@nih.gov SCHEDULE SUMMARY Letter of Intent Receipt Date: February 15, 2002 Application Receipt Date: March 15, 2002 Peer Review Date: July, 2002 Council Review: September, 2002 Earliest Anticipated Start Date: September 30, 2002 APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) available at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable PDF format. Although applicants are strongly encouraged to begin using the 5/2001 revision of the PHS 398 as soon as possible, the NIH will continue to accept applications prepared using the 4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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 must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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: Lillian Pubols, Ph.D. Chief, Scientific Review Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Room 3208 Bethesda, MD 20892 Rockville, MD 20852(for express/courier service) Applications must be received by the application receipt date listed in the heading of this RFA. 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. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. Applicants are permitted, however, to use the 4/1998 revision of the PHS 398 for scheduled application receipt dates until January 9, 2002. If you are preparing an application using the 4/1998 version, please refer to the step-by-step instructions for Modular Grants available at http://grants.nih.gov/grants/funding/modular/modular.htm. Additional information about Modular Grants is also available on this site. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year (no more than $125,000 direct costs/year for R21 s). The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NINDS and NIDDK. 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 NINDS 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, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NINDS and NIDDK National Advisory Councils. 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: o 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. o The reasonableness of the proposed budget and duration in relation to the proposed research. o 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. o The adequacies of the proposed plan to share data, if appropriate. AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities, and program balance 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 are provided indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. 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 these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Effect of hypoglycemia on glial and neuronal cell function , is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 (NIDDK) and 93.853 (NINDS). Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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 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, 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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