Full Text PA-95-014 BASIC AND CLINICAL RESEARCH ON SLEEP AND WAKEFULNESS NIH GUIDE, Volume 23, Number 45, December 23, 1994 PA NUMBER: PA-95-014 (This PA has been reissued, see PA-05-046) P.T. 34 Keywords: Sleep Disorders Neurophysiology Neuroscience Etiology Pathophysiology National Heart, Lung, and Blood Institute National Institute on Aging National Institute on Alcohol Abuse and Alcoholism National Institute of Child Health and Human Development National Institute on Drug Abuse National Institute of Mental Health National Institute of Neurological Disorders and Stroke National Institute of Nursing Research PURPOSE Sleep disturbances affect a wide range of age groups and practically every segment of society is profoundly affected by the absence of healthful patterns of sleep and wakefulness. It is now apparent that sleep disorders, disturbances of sleep, and sleep deprivation are major public health concerns. Recent estimates suggest that as many as 40 million people may suffer from chronic or intermittent disorders of sleep. Many of these people remain undiagnosed and untreated, the consequences of which include reduced productivity, lowered cognitive performance, increased likelihood of accidents, higher risk of morbidity and mortality and decreased quality of life. Research in sleep and sleep disorders has increased steadily over the past decade and basic research is rapidly becoming relevant to clinical problems. However, despite this growth in sleep research, the neurobiological mechanisms underlying sleep and wakefulness and many of the clinical manifestations affected by sleep remain largely unknown. It is now recognized that the sleeping brain is not in an inactive phase of existence, but rather is undergoing a complex set of active physiological and behavioral processes. Improved understanding of the fundamental nature of sleep, how sleep affects neural function, and how the central nervous system is modified by sleep can begin to provide a means to primary prevention of sleep disorders to reduce the economic and social impact of sleep/wake disturbances, and to significantly improve life expectancy and overall quality of life of all people across the lifespan. The purpose of this broad based sleep research program announcement is to inform the scientific community of the interests of the various Institutes at the National Institutes of Health (NIH) and to stimulate, foster, and coordinate a wide range of basic and clinical studies on sleep and wakefulness as they relate to the missions of these Institutes. These areas include, but are not limited to: (1) the neuroscience and behavioral science of sleep; (2) the molecular and cellular mechanisms of sleep and circadian rhythms across the life span; (3) the development of sleep from fetal life through infancy; (4) the neurobiologic role of dreaming in humans; (5) the etiologic factors and pathophysiology of transient or persistent insomnia; and (6) the treatment of sleep disorders. 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 Program Announcement, Basic and Clinical Research on Sleep and Wakefulness, is related to the fundamental research areas of the Decade of the Brain, and to the priority areas of chronic disabling conditions, mental health and disorders, and clinical prevention services. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, 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. Foreign institutions are not eligible for small research grants (R03s), First Independent Research Support and Transition (FIRST) (R29) awards (R29s), and research program project (P01) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The mechanisms of support will be the investigator initiated research project grant (R01), FIRST award (R29), and small research grants (R03). To apply for support of a more broadly based multidisciplinary research program, the research program project (P01) mechanism is suggested. Policies that govern the research grants programs of the NIH will prevail. Details of eligibility for the different funding mechanisms vary. Applicants are strongly advised to contact the program official listed under INQUIRIES for additional information, particularly related to P01s and other specific application procedures. RESEARCH OBJECTIVES There are a number of research directions that could be pursued to provide new insights on the underlying neurobiological mechanisms and clinical manifestations of sleep and wakefulness. This program announcement seeks to stimulate and encourage ideas that can compete successfully for support through grants-in-aid from the NIH. The following examples of research topics, many of which may lend themselves to studies in humans as well as in animal models and in vitro systems, are intended to reflect the breadth of interests of the NIH programs. Neurophysiological, behavioral, neuroanatomical, pharmacological, cellular, molecular and genetic techniques or combinations of these approaches are appropriate. All of the areas identified cut across Institutes and programs and should not be viewed as restricted to only one specific Institute. Current NIH referral guidelines will be used to assign grant applications to the most appropriate NIH Institute based on the scientific focus of the application. The National Center on Sleep Disorders Research (NCSDR) plans to coordinate sleep related activities at the NIH. The following topic areas are not intended to be comprehensive or exclusive: Neuroscience and Behavioral Science of Sleep. o Elucidate neural structures and mechanisms that control states of sleep and wakefulness. o Examine how neural circuits controlling sleep are modulated through emotions and stress, ethanol use or abuse, diseases or other disorders. o Obtain a better understanding of behavioral and physiological adaptations to sleep/wake cycles, hibernation, circadian and biological rhythms. o Determine neural correlates of cognition during sleep including learning and memory. o Utilize neural network models and theoretical approaches to understand the transitions between wakefulness and different stages of sleep. o Determine the homeostatic regulation of brain functions through interactions of sleep-promoting circuits in the brain. o Examine the role of sleep in understanding the basic neurobiology of substance and ethanol abuse. o Investigate the effects of drugs on the neurochemistry and determination of sleep onset, dreaming, awakening and transition between sleep and wakefulness. o Explore possible social factors and the development of sleep in children and adolescents as a model for acquiring behavioral control of homeostatic processes. Molecular and Cellular Mechanisms of Sleep and Circadian Rhythms Across the Life Span. o Identify genes, genetic mechanisms and heritable determinants in controlling sleep or circadian systems. o Isolate and characterize gene products that are expressed during sleep in order to identify molecules that alter intrinsic properties of neurons during this state of altered awareness. o Elucidate the mechanisms through which various stimuli, such as light, exercise, or endogenous factors (e.g., monoamines and melatonin) entrain sleep and circadian rhythms in mammalian and nonmammalian species, and any other sleep regulators such as the immune system and the suprachiasmatic nucleus. o Identify age related molecular, cellular and structural changes in the aging nervous system related to sleep and circadian systems. o Explore interventions, such as transplants of neuronal tissue, hormone or growth factor replacements to understand underlying mechanisms of age related alterations of sleep and circadian rhythms. o Apply noninvasive brain imaging techniques such as PET and MRI to identify changes in metabolism in specific brain areas, localize brain regulator mechanisms, and correlates of transitions between sleep states, dreaming and wakefulness during development and in the sleeping brain of older people. Development of Sleep from Fetal Life Through Infancy. o Determine the role of sleep and sleep state organization during fetal and infant development. o Identify potentially life threatening sleep disorders and dysfunctions which emanate specifically from chronic maternal use of alcohol, cigarette smoking and narcotic drugs. o Determine possible interactions between the developing immune system and the organization of sleep/wake state that occur in the first few months of life. o Explore the mechanisms underlying prenatal development of biological clocks and the relationship between maternal and fetal/neonatal behaviors necessary for establishing circadian rhythms. Neurobiologic Role of Dreaming in Humans. o Investigate the biological and behavioral functions and significance of dreams, including the role of REM sleep in mammalian evolution and memory. o Examine the role of non-REM sleep dreams and whether these are a qualitatively different type of brain activity than REM sleep dreams. Determine perceptual and cognitive influences on dream content. o Determine neural correlates of, and interactions between, sexual or other motivational systems, the content of dreams and sensory processing. o Employ multidisciplinary approaches utilizing metabolic and electrophysiologic methods to correlate events that occur during REM sleep with dreams involving non-visual sensory modalities. o Develop improved and more precise methods for identifying specific sleep stages, and the occurrence, onset and termination of dreams independent of waking recollections. o Correlate patterns of neuronal activity during REM sleep with dreams having other sensory modalities such as audition, olfaction or temperature regulation. o Develop better approaches to correlate subjective passage of time in a dream with real time duration. Etiologic Factors and Pathophysiology of Transient or Persistent Insomnia. o Investigate the role of the thalamus and other brain substrates in mediating insomnia. o Determine the relationship of insomnia to other medical conditions such as neurological, cardiovascular and psychiatric diseases. Determine physiological mechanisms that may account for the potential link between poor sleep, insomnia and cardiovascular disease, and whether insomnia may be predictive for future cardiovascular events. Examine the relationship of insomnia with other sleep disorders such as periodic movements of sleep and restless leg syndrome. o Investigate the role of persistent insomnia as a risk factor for development of depression and anxiety disorders. Determine the prognostic aspects of sleep for depression, alcoholism and other disorders; and the role of various sleep stages in predicting relapse following successful treatment of depression. Determine the mechanisms underlying the anti-depressant effect of sleep deprivation and changes associated with a night of recovery sleep. o Examine the effects of benzodiazepines on central nervous system acquisition or encoding of new information and the process of memory storage and recall. o Utilize sleep deprived, restricted, or disrupted models to understand the fundamental mechanisms of insomnia and effects on daytime function. Treatment of Sleep Disorders and Co-Morbidity with Other Conditions o Investigate the interactions between brainstem control of respiration and the neural mechanisms specific to sleep and wakefulness, and the source of the respiratory variations during sleep. o Investigate underlying autonomic mechanisms and physiological interrelations between snoring, obesity, sleep apnea, hypertension, and the regulation of sleep. o Determine the cellular and molecular basis of excessive daytime sleepiness, particularly as it relates to sleep apnea. o Explore the pharmacology and role of hormones in respiratory disorders of sleep. o Conduct studies on the efficacy of pharmacologic, behavioral and psychotherapeutic interventions for specific types of insomnia. o Investigate the risks, benefits, long term safety, and efficacy of hypnotic agents (i.e., benzodiazepines). Examine the long term efficacy of hypnotic agents in treating insomnia, especially whether the long term use renders them ineffective or if prolonged use actively disturbs sleep. Investigate the role of hypnotic agents on respiratory drive and autonomic function. o Determine the mechanisms underlying rebound insomnia and whether or not long term use of hypnotic agents leads to risk of physical dependence. o Develop and evaluate the best outcome variables and parameters to assess the clinical significance for insomnia therapy. o Understand co-morbidity of sleep disorders with neurological disorders to include but not limited to epilepsy, stroke, and movement disorders. o Examine the effects of ethanol use on respiratory function during sleep (e.g., sleep apnea). o Investigate the effects of sleep deprivation and use of ethanol and other drugs of abuse on daytime drowsiness and behavioral performance. o Understand co-morbidity of sleep and mental disorders o Explore mechanisms of environmental causes of sleep disturbances such as drug abuse, stressors, toxins, or artificial zeitgebers. o Investigate sleep disorders in underserved and understudied populations. o Investigate therapies that will ameliorate or eliminate sleep disorders due to disruptions of circadian rhythms. o Characterize sleep disturbances in persons with physical disabilities that result from traumatic injuries or chronic disease and how they influence the course of rehabilitation. 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 justifications is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/435-0714. The title and number of the program announcement must be typed in Section 2a on the face page of the application. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. The completed original application and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be reviewed for scientific and technical merit in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by the appropriate national advisory council or board. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non- competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. Review Criteria The following criteria will be considered when assessing the scientific/technical merit review of a research grant application: o Scientific, technical, or medical significance and originality of proposed research; o Appropriateness and adequacy of the experimental approach and methodology; o Qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o Availability of the resources necessary to perform the research. o Appropriateness of the proposed budget and duration in relation to the proposed research; The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to that IC. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Andrew A. Monjan, Ph.D., M.P.H. Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Suite 3C307 Bethesda, MD 20892 Telephone: (301) 496-9350 Email: MonjanA:NIA-GW:NIH Ellen D. Witt, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 402 6000 Executive Boulevard Rockville, MD 20892 Telephone: (301) 443-4223 Email: ewitt@willco.niaaa.nih.gov Marian Willinger, Ph.D. Pregnancy and Perinatology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B03 Bethesda, MD 20892 Telephone: (301) 496-5575 Email: willingm@hd01.nichd.nih.gov James R. Cooper, M.D. Division of Clinical Research National Institute on Drug Abuse Parklawn Building, Room 10A-12 5600 Fishers Lane Rockville, MD 20857 Telephone: (301) 443-4877 Email: jcooper@aoada.ssw.dhhs.gov James P. Kiley, Ph.D. Division of Lung Diseases National Heart, Lung and Blood Institute Westwood Building, Room 6A15 Bethesda, MD 20892 Telephone: (301) 594-7443 Email: james_kiley@nihh311.Bitnet Richard K. Nakamura, Ph.D. Coordinator for Sleep Research National Institute of Mental Health 5600 Fishers Lane, Room 11-102 Rockville, MD 20857 Telephone: (301) 443-1576 Email: NRN@CU.NIH.GOV Charlotte McCutchen, M.D. Epilepsy Branch, DCDND National Institute of Neurological Disorders and Stroke Federal Building, Room 114 Bethesda, MD 20892 Telephone: (301) 496-1917 Email: c5m@cu.nih.gov Mary Lucas Leveck, Ph.D. Acute and Chronic Illnesses Branch National Institute of Nursing Research Building 45, Room 3AN-12 Bethesda, MD 20892-6300 Telephone: (301) 594-5963 Email: mleveck@ep.ninr.nih.gov Direct inquiries regarding fiscal matters to: Crystal Ferguson Grants Management Office National Institute on Aging Gateway Building, Suite 2C212 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 (Courier Zip: 20814) Telephone: (301) 496-1472 Email: Ferguson%nihniagw.bitnet@cu.nih.gov Linda Hilley Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 504 MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-0915 Email: LHILLEY@willco.niaaa.nih.gov Douglas Shawver Office of Grants and Contracts National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17 Bethesda, MD 20892 Telephone: (301) 496-1303 Email: SHAWVERD@HD01.NICHD>NIH>GOV Gary Fleming Grants Management Branch National Institute on Drug Abuse Parklawn Building, Room 8A-54 5600 Fishers Lane Rockville, MD 20857 Telephone: (301) 443-6710 Email: gfleming@aoada.ssw.dhhs.gov Raymond L. Zimmerman Grants Management Branch National Heart, Lung, and Blood Institute Westwood Building, Room 4A17A Bethesda, MD 20892 Telephone: (301) 594-7420 Email: raymond_zimmerman%nihhwb1.bitnet@cu.nih.gov Diana Trunnell Grants Management Branch National Institute of Mental Health 5600 Fishers Lane, Room 7C-08 Rockville, MD 20857 Telephone: (301) 443-3065 Email: DT21A@NIH.GOV Karen Shields Grants Management Branch National Institute of Neurological Disorders and Stroke Federal Building, Room 1004 Bethesda, MD 20892-9190 Telephone: (301) 496-9231 Sally A. Nichols Grants Management Officer National Institute of Nursing Research Building 45, Room 3AN-32 Bethesda, MD 20892-6301 Telephone: (301) 594-7498 Email: USN@CU.NIH.GOV AUTHORITY AND REGULATIONS This project 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 PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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