BASIC RESEARCH TO IMPROVE CARDIOPULMONARY AND NEUROLOGICAL OUTCOMES FOLLOWING RESUSCITATION FROM CARDIOPULMONARY ARREST Release Date: September 7, 2001 RFA: RFA-HL-02-003 National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov) National Institute of Neurological Disorders and Stroke (http://www.ninds.nih.gov) Letter of Intent Receipt Date: January 10, 2002 Application Receipt Date: February 12, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT https://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE This RFA supports novel basic research designed to elucidate effects of whole-body ischemia and subsequent blood flow restoration on cardiovascular and neurological function. The ultimate goal is to provide a rational basis for development of effective new therapeutic strategies to restore heart function and preserve neurological function after cardiopulmonary arrest. 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), 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/. 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. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research 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 RFA may not exceed four years. 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. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at https://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE The NHLBI intends to commit $3 million total costs in FY2002 to award up to 8 new grants submitted in response to this announcement. NINDS will contribute up to $1 million total costs in FY2002 for award of up to 3 new grants. An applicant may request a project period of up to four years and a budget for direct costs of up to $250,000 (10 modules) per year, including facilities and administrative (F&A) costs on consortium arrangements. Because the nature and scope of the research proposed may vary, the amount of each award should also be expected to vary. Although the financial plans of the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds in each fiscal year, and receipt of a sufficient number of meritorious applications. RESEARCH OBJECTIVES Background Chances of survival following cardiac arrest are poor. Although the average time from arrest to defibrillation by trained medical personnel in large American cities have decreased dramatically to as short as 16 minutes, the survival rate following out-of-hospital arrest continues to be less than five percent. Thus, despite marked decreases in the time before initiation of medical aid to arrest victims, there remains tremendous need for development of new, effective interventions to restore blood flow to vital body organs including the heart and brain following cardiopulmonary arrest. New interventions should, in addition to restoring the heart beat, minimize and prevent irreversible cardiac and cerebral damage due to oxygen deprivation that may be exacerbated by restoration of blood flow throughout the body. Any advances in therapy for cardiopulmonary arrest require an improved basic science understanding of the pathophysiology of whole-body ischemia and subsequent reperfusion injury. Cardiac arrest, and the resulting whole-body ischemia, creates a unique state that affects many distant, otherwise healthy organs, including perturbations in systemic blood pH and compromised cerebral, renal, and pulmonary function, as well as a multitude of other poorly understood pathophysiologic alterations. Such changes may have a significant impact on cardiovascular and neurologic functions, particularly once blood flow is restored. The global changes to the internal milieu and distinct organ systems are difficult to mimic in isolated organ paradigms and other in vitro preparations. Understanding of the molecular, cellular, and biochemical interactions initiated within the heart, brain, and the other essential organs of these organs by whole-body ischemia should ultimately lead to amelioration and prevention of irreversible damage and allow successful cardiopulmonary resuscitation. Recently, several concepts drawn from fundamental investigations, cardiothoracic surgical experiences, and cardiac arrest studies, provide directions for the development of new therapeutic strategies to improve cardiac and neurological outcomes after cardiac resuscitation and to restore function following cardiopulmonary arrest, whole-body ischemia, and restoration of blood flow throughout the entire body. These new directions include reducing: (1) cardiac metabolic demands to allow additional time for the arrest victim to receive in-hospital medical treatment to restore heart function, (2) reducing the effects of cardiac ischemia and reperfusion injury, and (3) optimizing cardiac defibrillation effectiveness. The effects of these procedures on subsequent cardiovascular and brain function, including stroke, hemorrhage or neurocognitive consequences, in survivors have yet to be evaluated. These new research avenues were the basis for discussion during the Post-Resuscitation and Initial Utility in Life Saving Efforts (PULSE) workshop, sponsored in part by the NHLBI in the summer of 2000 and summarized in the published Workshop Executive Summary Report (Circulation 2001;103:1182-1184). One strategy to improve cardiopulmonary resuscitation outcomes might include induction of a temporary hypo-metabolic state of "hibernation" to both halt progression of arrest-initiated pathological processes and to prolong the time for additional medical interventions to restore cardiac and brain circulation and function. Hypothermia, for instance, slows destructive enzymatic reactions, suppresses the destructive effects of free radicals, and alters lipoprotein membrane complianceB all organ-protective effects. Understanding the arrest-induced metabolic perturbations and their consequence in the setting of reduced metabolic demands could lead to the development of biochemical or pharmacologic methods to dramatically reduce ischemic and reperfusion damage induced by cardiopulmonary arrest. Interventions that ameliorate reperfusion injury following resuscitation represent another possible strategy to improve resuscitation of cardiovascular and neurologic function following arrest. Cardiac surgical experience suggests that extracorporal control of reperfusion protects against myocardial damage during whole-body ischemia and reperfusion. Experimental data also suggests that certain drug combinations mitigate ischemia/reperfusion damage and mimic the protective effects of ischemic preconditioning. Such drug combinations might include: antioxidants, drugs that block the leukocyte-endothelial cell cascade, antibodies to neutrophil adhesion molecules, and agents that modify ion channel, exchanger, and pump activities. The effectiveness of such methods to control cardiac reperfusion and drug combinations to curtail myocardial, cerebrovascular, or neuronal ischemia/reperfusion injury need to be examined in appropriate models of whole-body ischemia. Another approach to improving cardiopulmonary resuscitation outcomes could be to limit the apoptotic process following whole-body ischemia and restoration of whole body blood flow. In models of acute myocardial ischemia, caspase inhibitor administration prior to ischemia decreases myocyte apoptosis and infarct size. Transgenic mice with cardiac overexpression of a protein that inhibits cytochrome c release and subsequent caspase activation exhibit less myocyte apoptosis and smaller myocardial infarcts following ischemia-reperfusion. Inhibition of cardiocyte apoptosis, therefore, may provide a novel approach for reducing both cardiac ischemic damage and myocardial reperfusion injury. Similarly, research on the roles of the various caspases in focal and global cerebral ischemia indicates that this enzyme cascade can activate both cell death and survival mechanisms in neurons. Further research on the involvement of caspases in cells of the cerebrovascular/neuronal unit is needed. New, improved methods to restore and preserve heart rhythm following cardiopulmonary arrest would result from improved understanding of the effects of whole-body ischemia and restoration of blood flow to the entire body. Although rapid defibrillation is standard care for cardiac arrest, successful defibrillation rates rapidly decrease as the period of myocardial ischemia following arrest increases. In addition, cardiac surgeons note that dilated hearts are difficult to defibrillate; the question arises as to whether biomechanical factors also play an important role in determining defibrillation success or failure following arrest. Understanding interactions between whole-body ischemia, optimal defibrillation thresholds, and restoration of blood flow to the body appear critical to successful defibrillation and cardiac resuscitation. Research Scope Novel approaches to better understand the effects of whole-body ischemia and restoration of whole-body circulation on cardiovascular performance and neurological involvement, and the application of these findings to development of effective new strategies to improve cardiopulmonary resuscitation are sought. New research collaborations are encouraged. Some examples of research that might address the effects of whole-body ischemia on cardiovascular and neurologic functions and how they may be ameliorated to reduce or prevent ischemia/reperfusion injury during resuscitation from cardiopulmonary arrest include: o characterization of the molecular, biochemical, and physiologic alterations in heart and brain function initiated by whole-body ischemia and how they may be affected by restoration of whole-body blood flow, o development of interventions to inhibit or limit the detrimental effect of whole body ischemia, such as the rapid induction of hypometabolic states, on restoration of heart and brain function in the setting of whole-body ischemia/reperfusion, o development of models of whole-body ischemia and whole-body blood flow restoration to mimic the effects of cardiopulmonary arrest and allow testing of the effectiveness of promising experimental interventions to effectively restore heart and brain function, o studies to evaluate experimental treatments that may have differential effects on heart and brain outcomes following whole body ischemia and restoration of blood flow, o development of effective defibrillation techniques in the setting of whole-body ischemia and restoration of blood flow to the entire body, and o utilization of genetically altered animal models to elucidate the integrated role of specific gene products and signaling systems in determining the cardiovascular and neurologic responses to whole-body ischemia and reperfusion. SPECIAL REQUIREMENTS For applications to be considered responsive to this RFA, proposed studies need to address the effects of whole body ischemia / reperfusion on cardiopulmonary or neural function. Studies that focus on the effects of cardiac or cerebral ischemia / reperfusion (i.e., regional or focal organ ischemia / reperfusion) alone will not be considered responsive and will be returned to the applicant without further consideration. In addition to yearly progress reports, the Principal Investigators of grants funded under this RFA will be expected to participate in yearly grantee meetings to present findings of the research supported and suggest future research directions. Funds for travel to such meetings must be incorporated in the standard NIH travel allowance for principal investigators. 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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at https://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: https://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: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLs IN NIH GRANTS 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: https://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. 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 this RFA. 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 NHLBI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Beebe at the address listed under INQUIRIES by January 10, 2002. APPLICATION PROCEDURES 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 https://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions beginning on page 13 of the application instructions. 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: https://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 as well as all five collated sets of Appendix material must be sent to Dr. Deborah Beebe at the address listed under Inquiries. 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. Principal investigators should not sent supplementary material without first contacting the Scientific Review Administrator (SRA). The SRA will be identified in the letter sent to you indicating that your application has been received. If you have not yet received such a letter within three weeks after submitting the application, contact Dr. Deborah Beebe at the address listed under Inquiries. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. 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 NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applicants 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 National Heart, Lung, and Blood Advisory Council and the National Advisory Neurological Disorders and Stroke Council. 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 their 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. Because of the nature of this RFA, and application must be judged to be innovative to deserve a high priority score. (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. If the proposed research includes studies in human subjects, 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. Schedule Letter of Intent Receipt Date: January 10, 2002 Application Receipt Date: February 12, 2002 Peer Review Date: June/July 2002 Council Review: September 2002 Earliest Anticipated Start Date: September 30, 2002 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 program 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: David A. Lathrop, Ph.D. Division of Heart And Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 9186 (MSC 7940) Bethesda, MD 20892-7940 (20817 for Courier) Telephone: (301) 435-0504 FAX: (301) 480-1454 Email: LathropD@nhlbi.nih.gov Mariana Gerschenson, Ph.D. Division of Heart And Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 9180 (MSC 7940) Bethesda, MD 20892-7934 (20817 for Courier) Telephone: (301) 435-0515 FAX: (301) 480-1336 Email: GerscheM@nhlbi.nih.gov Mary Ellen Michel, Ph.D. National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 2222, MSC 9525 6001 Executive Boulevard Rockville, MD 20892-9525 (20852 for Courier) Telephone: (301) 496-1447 FAX: (301) 480-1080 Email: mm108w@nih.gov Send letter of intent and 2 copies of the application and direct inquiries regarding review matters to: Deborah P. Beebe, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr., Room 7178 (MSC 7924) Bethesda, MD 20892-7924 (20817 for Courier) Telephone: (301) 435-0270 Fax: (301) 480-3541 Email: BeebeD@nhlbi.nih.gov Direct inquiries regarding fiscal matters to: Ms. Teneshia Alston Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7156, MSC 7926 Bethesda, Maryland 20892-7926 Telephone: (301) 496-6740 FAX: (301) 480-3310 E-mail: AlstonT@nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837 and 93.853. 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 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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