During the last 18 years of funding of this program project, the only NIH supported program project focused on narcolepsy, we have made significant strides in understanding the pathophysiology of narcolepsy, as well as the physiology of normal sleep. Our discovery during the last funding period that most cases of human narcolepsy cataplexy are caused by hypocretin (also called orexin) deficiency significantly changed the sleep field. In this revised competitive renewal proposal, based on our recent discoveries, we have refocused our research efforts and recruited new members to expand the expertise of the Center. In this revised proposal, we have brought together a unique group of independent investigators working across disciplines toward a common goal. Based on the reviewers' critiques, we have removed two projects from our original proposal, leaving four projects and a core (Project A). The core (Project A) provides the necessary core resources to support research projects at the Stanford Center for Narcolepsy, most notably biological samples. The goal of Project B, directed by Dr. Terry Young at the University of Wisconsin, Madison is to determine the prevalence of narcolepsy without cataplexy using an epidemiological approach and to study its association with HLA and lypocretin deficiency. Project D, directed by Dr. Juliette Faraco, will use a zebrafish model to isolate novel genes regulating hypocretin and histamine neurotransmission. In Project F, directed by Dr. Luis de Lecea, the discoverer of hypocretins, is seeking to identify novel genes with preferential expression in hypocretin-containing cells; an accessory goal of this project will be to study the neuropathology of narcolepsy without cataplexy. Project E, directed by Dr. Joachim Hallmayer, will use a human genetic approach to identify novel narcolepsy susceptibility genes. Narcolepsy is a frequent and disabling neurological disorder affecting more than 1 in 2,000 Americans. Our recent findings have led to new diagnostic procedures but have not yet changed therapeutic options. Our aims are improved diagnosis, a better understanding of the narcolepsy pathophysiology and the discovery of new treatments, if not a cure for narcoleptic patients. PROJECT A PI: Emmanuel Mignot Title: Research Administration Core, Human DNA Samples Bank, Animal Models, & Databases Description (provided by applicant): A seasoned and well-trained research administration staff is essential for the effective management of a complex multi-disciplinary program project. During the last consecutive 18 years of funding of this program project the Principal Investigator and the Assistant Director of the Sleep Research Center have worked together and built a team of research administrators and research support staff that are responsible for the day-to-day activities of managing the Center for Narcolepsy. This includes budgetary and fiscal reporting planning, oversight of policy and guidelines, animal and human database management, subject recruitment and the integration of this project into the Sleep Research Center and Sleep Clinic, and in general ensuring that the program runs smoothly. To support this revised research proposal, five main core activities are recognized: 1) A research administrative and coordinating function to facilitate the research & interactions among investigators and projects 2) Management of the Stanford University Center for Narcolepsy animal colonies used in this proposal; this includes zebrafish, mice, and rats. 3) Recruitment of human narcolepsy patients for research projects: this includes the banking of DNA, serum, cerebrospinal fluid and brain specimens from narcolepsy and control subjects. 4) Maintenance of computerized databases containing human, mouse/rat, canine narcolepsy data and tissue sample data; maintenance of the project's website and data-sharing on-line. 5) Maintenance of all documentation supporting adherence to all federal guidelines and policies for conducting research. It is the responsibility of the Principal Investigator to assure that the Center for Narcolepsy scientists work as an integrated team. His direction and scientific leadership, is essential to the pursuit of the overall goals of the program. A weekly research meeting is held to facilitate communication among the investigators and between the research staff and research administration staff.