INTERRELATIONSHIP BETWEEN SLEEP AND HEART, LUNG, AND BLOOD DISEASES Release Date: September 27, 2001 RFA: RFA-HL-01-009 National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/) National Institute on Drug Abuse (http://www.nida.nih.gov/) Letter of Intent Receipt Date: December 14, 2001 Application Receipt Date: January 24, 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 One goal of this Request for Applications (RFA) is to elucidate characteristics of sleep physiology, sleep disorders, and pathophysiological mechanisms mediating the interrelationship between sleep disturbance and heart, lung, and blood diseases. The specific objectives of this program are to identify measurable characteristics of sleep potentially useful for the investigation of heart, lung, blood, and sleep disorder pathogenesis; for diagnosis of these disorders, for therapeutic stratification of patients; and for assessing treatment efficacy. Another goal of this RFA is to identify markers of sleep disturbances produced by the use of psychoactive substances. Useful biomarkers might reflect the risk, presence, or severity of sleep abnormalities, and the relationship of sleep to progression or exacerbations of disease. A variety of techniques might be employed, ranging from proteomic analysis of tissue to functional imaging of brain, heart, vasculature, or lungs. The focus of this RFA is on novel biomarkers of sleep that can be determined by minimally invasive means and have the potential to facilitate basic and clinical studies of heart, lung, blood, and sleep disorders. 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), Interrelationship Between Sleep and Heart, Lung, and Blood Diseases, 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 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 This RFA will use the National Institutes of Health (NIH) 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 earliest anticipated award date is September 30, 2002. FUNDS AVAILABLE The National Heart, Lung, and Blood Institute (NHLBI) intends to commit approximately $3.1 million, and the National Institute on Drug Abuse (NIDA) intends to commit $375,000 in FY 2002 to fund seven to nine 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 not to exceed $250,000 per year (10 modules of $25,000 per year). Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. The financial plans of the NHLBI and the NIDA provide support for this program, however, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. Although the National Institute of Mental Health (NIMH, http://www.nimh.nih.gov/) will not participate in this RFA, NIMH has a shared interest in some topics covered by this RFA. NIMH will continue to fund these areas through the regular investigator-initiated mechanisms. RESEARCH OBJECTIVES Background Sleep related problems represent a severe health concern for millions of Americans and all age groups. Sleep disturbances reduce productivity and quality of life; increase the likelihood of workplace, home, and vehicular accidents; and are associated with a higher risk of morbidity and mortality. Sleep has a fundamental physiological role in neural, metabolic, immunological, and behavioral processes associated with normal health and maturation. However, relatively few biological functions of sleep have been elucidated. Sleep abnormalities such as excessive sleepiness, disturbed sleep, and inability to sleep occur in close association with a variety of diseases. Mutually exacerbating effects of sleep abnormalities and primary illness may be a significant barrier to recovery. While sleep abnormalities and excessive daytime sleepiness are recognized as an important clinical symptom of many illnesses, the role of sleep abnormalities in the pathophysiology of disease has not been widely studied. Polysomnographic and behavioral methods, used to assess sleep pattern abnormalities, need to be supplemented by additional biological correlates to investigate mechanisms underlying specific risks to health. The identification of measurable characteristics of sleep and its interrelationship with other physiological systems is needed to facilitate epidemiological and clinical studies, provide improved diagnostic tools, and stimulate the development of innovative therapies. Sleep disordered breathing ranging from chronic snoring to repeated interruptions in breathing (sleep apnea) is a common sleep disorder. Several lines of converging evidence associate sleep disordered breathing with a broad array of metabolic, vascular, hematological, and genetic markers associated with increased cardiovascular disease and stroke risk. Sleep apnea produces a lightening in sleep state, abrupt increases in blood pressure, and may be a secondary cause of hypertension. Vascular response to bradykinin, a vasodilator, is blunted in sleep apnea patients, and the level of a potent vasoconstrictor peptide, endothelin-1, appears to be elevated. Another factor contributing to increased vascular morbidity in sleep apnea patients may be elevated levels of fibrinogen, a liver protein enhancing thrombosis and atherosclerosis. Ischemic stroke patients with sleep apnea exhibit elevated plasma fibrinogen levels suggesting that inflammation or hypercoagulation may contribute to the increased risk of stroke in sleep apnea. Apolipoprotein E epsilon4 (apoE epsilon4), a genetic marker previously linked to cardiovascular disease risk, is associated with a two fold increased risk of sleep apnea, and an increase in the severity of apnea symptoms. The association between apoE epsilon4 marker, cardiovascular diseases, and sleep apnea suggests a possible common pathophysiological pathway involving lipid metabolism. Leptin, an anti-obesity hormone produced by adipose tissue, is significantly higher in obese subjects with sleep apnea. Animal studies suggest that obesity-related leptin resistance may contribute to sleep apnea pathophysiology by depressing respiration and chemosensitivity. A variety of cardiopulmonary and other diseases including those associated with psychoactive drugs are affected by and affect the quality of sleep. Intermittent sleep disturbances (arousals) alter cerebral blood flow and cause abnormalities in the circadian secretion of hormones that diminish resilience to stress and the ability to regulate blood glucose. Diabetes is associated with disturbed sleep, and partial sleep deprivation of otherwise healthy adults increases insulin resistance. Findings from the NHLBI Cardiovascular Health Study indicate that there is a strong association between daytime sleepiness and cardiovascular disease-related morbidity and mortality, myocardial infarction, and congestive heart failure. Accumulating evidence suggests that enhancing sleep quality in patients with heart failure reduces sympathetic outflow and helps to preserve myocardial function. Thrombotic events are more likely to occur during sleep or awakening, and are believed to be a major cause of stroke and heart attack. The level of circulating cell subtypes in blood varies with sleep and sleep deprivation. Asthma may worsen during sleep for various reasons and the majority of asthma deaths occur during normal sleeping hours. Bronchitis, emphysema, and interstitial lung disease also impede sleep. Infection and inflammation induce symptoms of excessive daytime sleepiness and fatigue. The use of psychoactive drugs is associated with abnormalities in sleep pattern. Recovering addicts often experience persistent sleep disturbances that contribute to the risk of relapse. Research Scope Recent advances in understanding how sleep is regulated and coupled to other physiological systems have provided a foundation on which to further develop our understanding of potential pathophysiological relationships. Research is needed to identify measurable characteristics of sleep and related biomarkers that are significant in relation to cardiopulmonary and hematological disease pathophysiology, sleep disorders, and sleep deprivation in children and adults. Identification of measurable sleep characteristics that change during illness should allow interrelationships between sleep and disease to be studied by a broad community of cardiovascular, pulmonary, hematological, and sleep researchers. Such characteristics could potentially serve as indicators of disease risk, severity, progression, prognosis, and response to treatment. Identifying pathophysiologic indicators associated with excessive daytime sleepiness, nonrestorative or poor sleep during acute or chronic disease conditions will provide the groundwork to determine how disease causes sleep abnormalities and vice versa. Listed below are examples of studies that would be responsive to this program. These are only illustrative examples and applicants are encouraged to consider other topics consistent with the goals of this program. Not all areas need to be addressed in a single application. Identify measurable characteristics of sleep that o Facilitate studies of the function of sleep, the interrelationship between sleep and other physiological systems, and the integration of epidemiologic and clinical information; o Reflect early pathophysiological consequences of excessive daytime sleepiness due to abnormalities in sleep timing, pattern, or duration. o Predict the risk, progression, or prognosis of sleep, heart, lung, and blood disorders. o Reflect individual susceptibility to excessive daytime sleepiness and to sleep abnormalities o Are useful for the diagnosis or prevention of sleep related morbidity and for assessing the progression of sleep disorders and the effectiveness of therapy. o Are associated with insomnia and other sleep disturbances produced by the use of psychoactive substances. SPECIAL REQUIREMENTS For the purpose of this RFA, a biomarker is defined as a qualitatitive or quantitative indicator of biological, physical, anatomical, chemical, or cellular changes contributing to the understanding of disease pathogenesis or risk. Among the approaches this definition permits are the following: o Proteomic analyses, o Gene expression profiles, o Neurophysiological analyses, o Identification of genetic markers, o Cellular and biochemical profiles of tissues or biological fluids, and o Functional imaging technologies such as magnetic resonance, positron emission tomography, or magnetoencephalography. In order to be considered responsive to this announcement, applications must propose hypothesis-driven studies that focus on elucidating measurable characteristics of sleep physiology, sleep disorders, or pathophysiological mechanisms mediating the interrelationship between sleep disturbance and cardiovascular, pulmonary, immunological, or hematological health. Studies to identify genetic markers of this interrelationship will also be responsive. Biomarkers that can be determined by minimally invasive means and have the potential to facilitate epidemiological studies of cardiovascular, pulmonary, hematological, and sleep disorders are encouraged. Studies proposing the use of nonmammalian species or in vitro preparations should clearly establish the relationship of these models to the goals set forth in this RFA. Collaborations and consortia promoting interdisciplinary approaches between scientists studying sleep medicine, cardiology, pulmonology, hematology, neuroimmunobiology, infectious disease, endocrinology, genetics, and neurophysiology are strongly encouraged. In such cases, each participant's contribution should be identified and well-integrated into the overall experimental design. The elucidation of environmental factors producing sleep abnormalities such as shift work, rapid time zone changes, cultural and socioeconomic factors will not be supported under this RFA. Studies of alcohol abuse, pain syndromes, cancer, mental disorders, and the relationship of sleep to behavioral endpoints such as workplace performance would also be unresponsive to this RFA. Applications focused on the development of methodology, large clinical studies, or the establishment of large epidemiological cohorts that collect data for future studies are not within the scope of this program. 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 the principal investigator to attend 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 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 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: 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 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 NHLBI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Deborah Beebe (see address listed under Inquiries below) by the letter of intent receipt date listed. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at https://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. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. 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 https://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. 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 sample RFA label available at: https://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 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. 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. Principal investigators should not send 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, contact Dr. Deborah Beebe at the address listed under Inquiries. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. If the application is not responsive to the RFA, NHLBI staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in the regular competition for 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, 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 National Advisory Councils of the NHLBI and/or NIDA. 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: December 14, 2001 Application Receipt Date: January 24, 2002 Peer Review Date: April, 2002 Council Review: August, 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 programmatic priorities. 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: Michael Twery, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Rockledge 2, Suite 10018 6701 Rockledge Drive, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0202 FAX: (301) 480-3557 Email: mt2d@nih.gov Harold Gordon, Ph.D. Division of Treatment Research and Development National Institute on Drug Abuse Neuroscience Center, Room 4233 6001 Executive Boulevard, MSC 9559 Rockville, MD 20892-9559 Telephone: (301) 443-4877 FAX: (301) 443-6814 Email: hg23r@nih.gov Direct inquiries regarding review issues to: Deborah Beebe, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr.,Room 7178 (MSC 7924) Bethesda, MD 20892-7924 Telephone: (301) 435-0270 Fax: (301) 480-3541 Email: db57j@nih.gov Direct inquiries regarding fiscal matters to: Robert Vinson 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: rv7g@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.233, 93.837, 93.838, and 93.839. 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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