RESEARCH GRANTS RELATED TO NARCOLEPSY NIH GUIDE, Volume 22, Number 5, February 5, 1993 PA NUMBER: PA-93-51 P.T. 34 Keywords: Sleep Disorders Etiology National Institute of Neurological Disorders and Stroke National Institute of Mental Health PURPOSE The Division of Convulsive, Developmental, and Neuromuscular Disorders; National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Mental Health (NIMH) are revising and reissuing a NINDS program announcement on narcolepsy published in the NIH Guide to Grants and Contracts, Vol. 19, No. 15, April 13, 1990, to notify the scientific community of continuing NINDS/NIMH interest in the submission of research project grant applications related to narcolepsy. 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 priorities. This program announcement is related to the priority area of narcolepsy. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: No. 017-001-00474-0, or Summary Report: Stock No. 017-001-00473-0) 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 institutions, 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 eligible for research project grants (R01) only. Applications from minority institutions, minority individuals, and women are encouraged. MECHANISM OF SUPPORT The support mechanisms for grants in this area will be the investigator-initiated research project grant (R01), the First Independent Research Support and Transition (FIRST) award (R29), the program project grant (P01), and the center grant (P50). As consistent with the aforementioned mechanisms, the Principal Investigator or program director, as well as any participating investigators, will plan, direct, and perform the research. Applicants for program project grants should contact the NINDS representative listed below as early as possible in the planning stages. RESEARCH OBJECTIVES Background Narcolepsy is a neurological condition characterized by irresistible episodes of sleep. The classic symptoms of narcolepsy are: (1) sleep attacks - sudden urges to sleep; (2) cataplexy - sudden generalized or partial flaccid paralysis; (3) hypnagogic hallucinations - sleep onset hallucinations; and (4) sleep paralysis - generalized paralysis before or at the time of falling asleep or on awakening. Narcolepsy has its typical onset in adolescence and young adulthood. There is an average 15-year delay between onset and correct diagnosis, that may contribute substantially to the disabling features of the disorder. Cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented. For these to occur in the crucial teen years when education, development of self-image, and development of occupational choice are taking place is especially damaging. While cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence. The prevalence of narcolepsy in the United States has been estimated to be as high as one per 1,000. It is a major reason for patient visits to sleep disorder centers, and with its onset in adolescence, it is also a major cause of learning difficulty and absenteeism from school. Normal teenagers often already experience excessive daytime sleepiness because of a maturational increase in physiological sleep tendency accentuated by multiple educational and social pressures; this may be disabling with the addition of narcolepsy symptoms in susceptible teenagers. In clinical practice, the differentiation between narcolepsy and other conditions characterized by excessive somnolence may be difficult. Treatment options are currently limited. There is a paucity in the literature of controlled double-blind studies of possible effective drugs or other forms of therapy. Mechanisms of action of some of the few available therapeutic agents have been explored but detailed studies of mechanisms of action are needed before new classes of therapeutic agents can be developed. The neural control of normal sleep states and the relationship to narcolepsy are only partially understood. In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to rapid eye movement (REM) sleep with little or no intervening non-REM sleep. The changes in the motor and proprioceptive systems during REM sleep have been studied in both human and animal models. During normal REM sleep, spinal and brainstem alpha motor neuron hypopolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway. Acetylcholine may be one of the neurotransmitters involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in cataplexy is believed identical to that seen in normal REM sleep. Despite the experimental evidence in human narcolepsy that there may be an inherited basis for at least some forms of narcolepsy, the mode of inheritance remains unknown. Research Goals and Scope The goal of this announcement is to stimulate research in both basic and clinical aspects of narcolepsy. The scope of this program encompasses both animal and human studies, that would utilize a variety of experimental approaches and methods. If experimental studies on human subjects are proposed, the protocols should contain recruitment procedures to encourage the participation of women and minorities. Examples of areas of potential research include studies on the pathophysiology of narcolepsy; abnormalities of circadian rhythms, particularly anatomical and biochemical substrates; the molecular genetics of narcolepsy; and the development of new therapies. New, more sensitive, and specific objective diagnostic procedures need to be developed and validated. While studies in the naturally occurring narcoleptic dog model suggest an autosomal recessive mode of transmission in that model, genetic analysis of cohorts of narcoleptic patients and identification of informative families are needed to define the mode of inheritance and to facilitate the search for gene markers. STUDY POPULATIONS POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder, or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders, and conditions that disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial or ethnic group. In addition, gender and racial or ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Sections 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups; however, the NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of Unites States racial or ethnic minority populations: Native Americans (including American Indians or Alaska Natives), Asian or Pacific Islanders, Blacks, and Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and prevention strategies), diagnosis, or treatment of diseases, disorders, or conditions, including, but not limited to, clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded; however, every effort should be made to include human tissues from women and racial or ethnic minorities when it is important to apply the results of the study broadly. This directive should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully. Since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' population, including minorities. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to the NIH are required to address these policies. If the required information is not contained within the application, the review will be deferred until the information is provided. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) according to the instructions included in the application package. These application packages are available at the institutional office of sponsored research and from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/496-7441. Applicants for program project grants (P01) should request, from the address below, a copy of the NINDS Guidelines: Program Project and Research Center Grants (rev. 6/92). Receipt dates for new research project grant (R01) applications and FIRST (R29) awards and for program project (P01) and center grant (P50) applications are February 1, June 1, and October 1. FIRST award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST award applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. On page 1 of form PHS 398, check "yes" in Item 2a, enter the number of this Program Announcement in the space provided, and the name of this Program Announcement (Narcolepsy) in the blank space labeled "Title." Use the mailing label provided in the application package to mail the signed original and five exact copies of it to the Division of Research Grants. REVIEW CONSIDERATIONS Research project grant (R01) applications and FIRST award (R29) applications will be reviewed for scientific and technical merit by an appropriate study section in the Division of Research Grants. Program project grant (P01) and center grant (P50) applications will be reviewed according to the practice of the Institute to which the application is assigned. The second level of review will be by the appropriate national advisory council. AWARD CRITERIA The standard review criteria will be used to assess the scientific merit of applications. Applications will compete for available funds with all other applications. The following will be considered when making funding decisions quality of the proposed projects as determined by peer review, availability of funds, and program balance among research areas. INQUIRIES Questions concerning neurological/neuroscientific aspects of this Program Announcement may be addressed to: Charlotte B. McCutchen, M.D. Division of Convulsive, Developmental, and Neuromuscular Disorders National Institute of Neurological Disorders and Stroke Federal Building, Room 114 Bethesda, MD 20892 Telephone: (301) 496-6701 FAX: (301) 402-0302 Questions concerning psychiatric aspects of the Program Announcement may be addressed to: Susan Blumenthal, M.D. Basic Prevention and Behavioral Medical Research Branch National Institute of Mental Health Parklawn Building, Room 11C06 Rockville, MD 20857 Telephone: (301) 443-4337 FAX: (301) 443-4822 Questions concerning fiscal aspects of this Program Announcement may be addressed to: Patricia Driscoll Grants Management Branch National Institute of Neurological Disorders and Stroke Federal Building, Room 1004 Bethesda, MD 20892 Telephone: (301) 496-9231 AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance, Number 93.853, Clinical Research Related to Neurological Disorders, and 93.854, Biological Basis Research in the Neurosciences. Grants will be awarded under the authority of the Public Health Service Act, Title IV, Section 301 (Public Law 78-410, as amended: 42 USC 241) and administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR 74. This program is not subject to Health Services Agency Review of the intergovernmental review requirements of Executive Order 12372. .
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