OXYGEN SENSING DURING INTERMITTENT HYPOXIA Release Date: November 29, 1999 RFA: HL-00-004 National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: January 24, 2000 Application Receipt Date: February 23, 2000 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 THIS RFA/PA. PURPOSE The purpose of this initiative is to improve our understanding of how intermittent hypoxia contributes to the pathophysiology of cardiopulmonary, vascular, hematological, and sleep disorders. Specific objectives are to determine the basic molecular and genomic mechanisms involved in cellular responses to brief intermittent hypoxic episodes including mechanisms responsible for the detection and signaling of oxygen level changes, and the mechanisms that mediate adaptive changes in metabolism, oxygen sensing, and gene expression. For the purpose of this announcement, intermittent hypoxia is defined as repetitive hypoxic episodes lasting up to two minutes. 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 Request for Applications (RFA), Oxygen Sensing During Intermittent Hypoxia, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. 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. Multiple applications from the same institution will not be considered for support under this program unless each application is submitted by a different principal investigator, and is self-contained and independent of other applications from that institution. Overlap in the scientific scope of applications from the same institution will not be accepted. This does not preclude cooperation among participants after awards are made. If more than one application is envisioned from an institution, the investigators are encouraged to discuss their plans with one of the program administrators listed under INQUIRIES. MECHANISM OF SUPPORT This RFA 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 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 according to the customary peer review procedures. The anticipated award date is September 30, 2000. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE The NHLBI intends to commit $3.6 million in FY 2000 to fund up to 14-16 new grants in response to this RFA. An applicant may request a project period of up to four years and a budget for direct costs of up to $175,000 (7 modules) per year, excluding facilities and administrative (F&A) costs on consortium arrangements. Because the nature and scope of the research proposed in each application may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the National Heart, Lung, and Blood Institute provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds, and the scope and merit of applications received. RESEARCH OBJECTIVES Background Recent progress in understanding the molecular bases of oxygen sensing mechanisms provides a strong foundation for studying cellular responses to intermittent hypoxia and characterizing its cumulative effects. Studies of oxygen sensing and signaling mechanisms based on models of continuous hypoxia may not be applicable to understanding physiological or pathological responses during intermittent hypoxic episodes such as in sleep apnea, central hypoventilation syndrome, apnea of prematurity, and vascular occlusion associated with sickle cell disease. Episodes of intermittent systemic or local hypoxia affect metabolic pathways, induce angiogenesis, and affect inflammatory responses. The inability of cells to detect and adapt rapidly to changes in oxygen may underlie various vascular, pulmonary, coronary, cerebral, and sleep disease states. Hypoxia has also been shown to modulate the activity of gene regulators, growth factors, and reactive oxygen species that serve as intermediary signals in the cellular response to oxygen level changes. Furthermore, cyclic reductions in blood oxygen saturation of 30-50% during sleep apnea are associated with blunted chemosensitivity, and increased risk of hypertension, myocardial infarction, cerebrovascular disease, and neurocognitive deficits. Research Scope New approaches and paradigms are needed to investigate the effects of intermittent oxygen depletion and reoxygenation in a wide variety of tissues and cell types. Little is known of the function of heme-containing compounds, membrane conductances, calcium homeostasis, and other elements in the metabolic and signaling cascade mediating chemotransduction during intermittent hypoxia. The function of the red blood cell and other blood components as oxygen-sensing units also needs to be characterized. Hypoxia-induced free intracellular calcium level changes have been closely related to alterations in mitochondrial function, signal transduction, transmitter secretion, and the regulation of gene expression. A number of genes have been identified whose transcription is markedly stimulated when cells continuously lack oxygen. Characterization of the effects of intermittent hypoxia on gene expression through oxygen sensitive protein kinases and other regulators of transcription is needed to better understand the mechanisms by which cells adapt and respond to changes in oxygen levels. The role of reactive oxygen species during intermittent hypoxia also needs to be investigated since much of the remaining oxygen may go to the production of intermediates that influence the signaling pathways between nucleus and mitochondria, mitochondrial function, blood vessel tone, and cell survival. Transgenic technologies that alter gene expression in specific tissues or in response to pharmacological stimulation could be used to address these issues. Clarification of the molecular events during intermittent hypoxia will help elucidate hypoxia-related pathology in a wide range of tissues. One fundamental question relates to the role of intermittent cycles of hypoxia and reoxygenation in disease. For example, sleep apnea is associated with congestive heart failure and reduced survival. We need to know whether intermittent hypoxia during heart failure exacerbates tissue injury through changes in vascular smooth muscle function, vascular permeability, or apoptotic cardiac cell death. Intermittent hypoxia may contribute to vascular or pulmonary inflammation. Developing biomarkers and imaging techniques that identify or assess these inflammatory changes should help in the early detection of disease. Hypoxia responsive genes are widely expressed during embryogenesis, regulate proliferation or differentiation of cells, and affect the development of critical systems such as glucose metabolism, hematopoiesis, and blood vessel development. There is a need for studies that characterize developmental effects of intermittent hypoxia on heart, lung, vascular, and blood tissues, and the maturation of central pathways regulating the function of these tissues. This RFA is designed to stimulate molecular, genomic, and biophysical approaches to studying the effects of intermittent hypoxia on gene expression, cellular signaling pathways, and oxygen sensing in a variety of tissues. Listed below are examples of studies that would be responsive to this program. These are only illustrative examples and applicants are encouraged to propose other topics consistent with the goals of this program. Not all areas need to be addressed in a single application. o Elucidation of the signal transduction, gene regulating, and mitochondrial mechanisms that mediate oxygen sensing during intermittent hypoxia in central and peripheral tissues, and of the time course and oxygen level threshold for adaptive changes in cellular, local, or systemic responses. o Elucidation of the role of intermittent hypoxia in tissue injury produced by alterations in mitochondrial electron transport, mitochondrial genome damage, or oxidant and excitotoxic stress contributing to heart, lung, blood, or sleep disorders. o Development and use of noninvasive approaches and biomarkers for tissue- specific mapping of changes in gene expression and the cellular injury produced by intermittent hypoxia, and to identify and assess oxidative injury and vascular inflammation in brain and other tissues at early time points in sleep apnea patients. o Development and use of animal models to elucidate the cellular mechanisms mediating effects of intermittent hypoxia on autonomic control of heart rate, cerebral blood flow, respiration, or the daily rhythm of cytokine-immune and endocrine function. o Identification and characterization of cellular mechanisms that may regulate vascular tone in response to intermittent hypoxia such as the nitric oxide synthase system and the microsomal electron transporting systems associated with P450 enzymes. o Identification and characterization of intermittent hypoxia effects on angiogenesis, the structure and permeability of the blood brain barrier, or the microvasculature of organ systems in newborns and adults. o Identification and characterization of mechanisms through which intermittent hypoxia contributes to either atherosclerotic or hypertensive diseases. o Elucidation of the pathophysiological role of intermittent hypoxia during vascular occlusion in sickle cell disease. o Identification and characterization of molecular events that follow intermittent, localized hypoxia in individuals with thrombosis. o Characterization of intermittent hypoxic effects on interactions between the hemostatic system and endothelium including changes in leukocyte adhesion. o Elucidation of the role of intermittent hypoxia and abnormal oxygen sensing in polycythemia vera. o Elucidation of molecular effects of intermittent hypoxia on hematopoiesis, including megakaryocyte development and platelet production. o Identification and characterization of oxygen sensing mechanisms in red blood cells that are responsive to intermittent hypoxia. SPECIAL REQUIREMENTS In order to be considered responsive to this announcement, applications must propose hypothesis-driven studies that address the molecular effects of brief intermittent systemic or local hypoxia (repetitive hypoxic episodes lasting up to two minutes) as it occurs in diseases like sleep apnea and sickle cell microvascular occlusions. If in vitro models are proposed, they must test the effects of intermittent hypoxia as defined in this announcement. Research should be linked to understanding the role of intermittent hypoxia in disorders affecting the heart, vasculature, lung, blood, or sleep. Studies to elucidate the effects of a single hypoxic episode, chronic hypoxia, or ischemia are not responsive to this RFA. Applications focused solely on the development of methodology without plans for addressing the goals of this RFA will not be accepted. Studies needed to develop biomarkers or to overcome barriers such as the development of instrumentation should be integrated into the proposed research program. Collaborations and consortia promoting interdisciplinary approaches between scientists studying the molecular biology of the carotid body and arterial oxygen sensing, genetics, vascular and sickle cell disease, immunology, and developmental biology are strongly encouraged. In such cases, each participant's contribution should be identified and well-integrated into the overall experimental design. Upon initiation of the program, periodic meetings will be organized to encourage the exchange of information among investigators who participate in this program. Travel funds for a two day meeting each year, most likely to be held in Bethesda, Maryland, must be included in the module calculation. Applicants must include a statement indicating their willingness to participate in these meetings. Applicants are encouraged to contact the program officials listed under INQUIRIES for further information. 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 was 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: http://grants.nih.gov/grants/guide/notice-files/not94-100.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://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. 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 avoid conflict of interest in the review. The letter of intent is to be sent to Dr. C. James Scheirer listed under INQUIRIES by the letter of intent receipt date listed in the heading of this RFA, January 24, 2000. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) 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 301/435-0714, email: GrantsInfo@nih.gov and on the internet at http://grants.nih.gov/grants/forms.htm. 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 Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $175,000 (7 modules) per year excluding F&A costs on consortium arrangements. 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: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $175,000) and Total Costs [Modular Total Direct plus F&A costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, List key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus F&A costs) for each year, each rounded to the nearest $1,000. List the individuals/ organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations; o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The RFA label available in the PHS 398 (rev. 4/98) application form must have the RFA number typed on it and be affixed to the bottom of the application face page. 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. A sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 Dr. C. James Scheirer 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. 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 or submitted for review in competition with unsolicited applications at the next review cycle. 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, a process will be used by the initial review group in which applications 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. 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. Schedule Letter of Intent Receipt Date: January 24, 2000 Application Receipt Date: February 23, 2000 Peer Review: June/July, 2000 Council Review: September 7-8, 2000 Anticipated Award Date: September 30, 2000 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 balance. 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 Twery, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Rockledge 2, Suite 10018 Bethesda, MD 20892-7952 Telephone: (301) 435-0202 FAX: (301) 480-3557 Email: TweryM@nih.gov Greg Evans, Ph.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10152 (MSC 7950) Bethesda, MD 20892-7950 Telephone: (301) 435-0055 FAX: (301) 480-0868 Email: EvansG@nih.gov Stephen Goldman, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10192 (MSC 7956) Bethesda, MD 20892-7956 Telephone: (301) 435-0565 FAX: (301) Email: GoldmanS@nih.gov Direct inquiries regarding review matters to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr.,Room 7220 (MSC 7924) Bethesda, MD 20892-7924 Telephone: (301) 435-0266 Fax: (301) 480-3460 Email: js110j@nih.gov Direct inquiries regarding fiscal matters to: Raymond Zimmerman Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154, MSC 7926 Bethesda, Maryland 20892-7926 Telephone: 301 435-0171 FAX: 301 480-3310 E-mail: ZimmermR@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837. 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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