Genomic Analysis in narcolepsy-Cataplexy

发作性睡病-猝倒症的基因组分析

• 批准号: 7661409
• 负责人: JOACHIM F HALLMAYER
• 金额: $ 37.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7661409
• 关键词: Accounting; Acids; Address; Adherence; Administrator; Adolescence; Adrenergic Agents; Affect; African American; Alleles; American; Animal Model; Animals; Antigen-Presenting Cells; Arabs; Asians; Autoimmune Process; Autonomic nervous system; Bioinformatics; Biological; Brain; Candidate Disease Gene; Canis familiaris; Case-Control Studies; Cataplexy; Caucasians; Caucasoid Race; Cells; Cerebrospinal Fluid; Characteristics; Child; Chronic Disease; Class; Clinic; Clinical Data; Code; Collaborations; Collection; Communication; Complex; Critiques; DNA; DNA Library; Data; Databases; Dextroamphetamine; Diagnosis; Diagnostic Procedure; Discipline; Disease; Documentation; Eating; Emotions; Ensure; Epidemiologic Studies; Epilepsy; Ethnic group; Europe; Excessive Daytime Sleepiness; Face; Family; Family Study; Family member; First Degree Relative; Frequencies; Functional disorder; Funding; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Screening; Genome; Genome Scan; Genomics; Genotype; Goals; Guidelines; HLA Antigens; Health; Histamine; Home environment; Human; Human Genetics; Hypnagogic Hallucination; Hypothalamic structure; Individual; International; Japanese Population; Jews; Knockout Mice; Lead; Leadership; Left; Lod Score; Maintenance; Maps; Metabolism; Methylphenidate; Modafinil; Modeling; Mus; Muscle Weakness; Narcolepsy; Neurons; Neuropeptides; Nucleotides; Numbers; Parents; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Physiology; Play; Policies; Population; Posterior Hypothalamus; Predisposition; Prevalence; Principal Investigator; Psyche structure; REM Sleep; Range; Rate; Rattus; Recruitment Activity; Regulation; Regulator Genes; Reporting; Research; Research Personnel; Research Project Grants; Research Proposals; Research Support; Research Training; Resolution; Resources; Risk; Role; Running; Sampling; Schools; Scientist; Seasons; Serum; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism in Coding Sequence; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Paralysis; Sleep Wake Cycle; Solid; Specimen; Support of Research; Susceptibility Gene; Symptoms; TNFRSF5 gene; Testing; Therapeutic; Time; Tissue Sample; Title; Transcript; Tricyclic Antidepressive Agents; Twin Multiple Birth; United States National Institutes of Health; Universities; Validation; Variant; Wakefulness; Wing; Wisconsin; Work; Zebrafish; adrenergic; animal colony; base; case control; computerized; day; ethnic difference; expectation; follow-up; genetic linkage analysis; genetic risk factor; hypocretin; improved; inhibitor/antagonist; interest; member; mutant; nervous system disorder; neuropathology; neurotransmission; novel; novel diagnostics; orexin B receptor; programs; psychosocial; rapid eye movement; reuptake; roentgen equivalent man; selective expression; sleep onset; sleep regulation; social; tool; transmission process

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：在该计划项目的最后18年中，唯一一项专注于发作性睡病的计划项目，我们在理解发肠疾病的病理生理学以及正常睡眠的生理学方面取得了长足的进步。在最后一个资金期间，我们的发现，大多数人性发作性疾病的瘫痪病例是由降囊蛋白（也称为Orexin）缺乏症引起的，这显着改变了睡眠场。根据我们最近的发现，在经过修订的竞争更新建议中，我们重新调整了研究工作，并招募了新成员来扩大该中心的专业知识。在这项修订的提案中，我们将跨学科工作的独特独立研究人员汇总为一个共同的目标。根据审稿人的批评，我们从原始提案中删除了两个项目，留下了四个项目和一个核心（项目A）。核心（项目A）提供了必要的核心资源，以支持斯坦福大学发肠疾病中心的研究项目，最著名的是生物样品。由威斯康星大学麦迪逊大学特里·扬（Terry Young）指导的项目B的目标是使用流行病学方法来确定无抗心理的发病率的流行，并研究其与HLA和Lypocretin缺乏症的关联。由朱丽叶·法拉科（Juliette Faraco）博士执导的项目D将使用斑马鱼模型来隔离调节低封素和组胺神经传递的新基因。在Project F中，由降压素的发现者路易斯·德·莱西（Luis de Lecea）指导的项目F正在寻求鉴定在含降压素细胞中优先表达的新型基因。该项目的附件目标是研究无瘫痪的麻醉症的神经病理学。 Joachim Hallmayer博士导演的E项目将使用人类遗传学方法来识别新型的麻醉症易感基因。睡病经常是一种影响2,000名美国人中超过1个以上的神经系统疾病。我们最近的发现导致了新的诊断程序，但尚未改变治疗选择。我们的目标是改善诊断，更好地理解睡病的病理生理学以及发现新疗法的发现，即使不是治疗麻醉剂的患者。 项目 PI：Emmanuel Mignot 职位：研究管理核心，人类DNA样品银行，动物模型和数据库 描述（由申请人提供）：经验丰富且训练有素的研究管理人员对于有效管理复杂的多学科计划项目至关重要。在该计划项目的最后18年的最后18年中，首席研究员和睡眠研究中心的助理主任共同努力，并建立了一个研究管理人员和研究支持人员团队，负责管理Narcolepsy中心的日常活动。这包括预算和财政报告计划，对政策和指南的监督，动物和人类数据库管理，受试者招聘以及该项目将该项目集成到睡眠研究中心和睡眠诊所，并且总体上确保该计划顺利进行。为了支持这项修订的研究建议，确认了五项主要的核心活动：1）研究和协调功能，以促进研究人员和项目之间的研究和互动2）该提案中使用的斯坦福大学鼻ropsy动物殖民中心的管理；这包括斑马鱼，小鼠和大鼠。 3）研究项目的人性疾病患者招募：这包括从麻醉和控制受试者中的DNA，血清，脑脊液和脑标本的库。 4）维护包含人类，小鼠/大鼠，犬类性睡病数据和组织样品数据的计算机数据库；维护该项目网站和数据共享在线。 5）维护所有文档，支持遵守所有联邦指南和进行研究的政策。首席研究人员有责任确保发肠病毒科学家中心担任综合团队。他的方向和科学领导对于追求该计划的整体目标至关重要。举行每周一次的研究会议，以促进研究人员之间以及研究人员和研究管理人员之间的沟通。