HLA-DQ Sequencing Studies in Narcolepsy/Hypocretin Deficiency

发作性睡病/下丘脑分泌素缺乏症的 HLA-DQ 测序研究

• 批准号: 7991554
• 负责人: Emmanuel J Mignot
• 金额: $ 39.58万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991554
• 关键词: Affect; African American; Alleles; American; Amino Acids; Antigen Presentation; Asians; Autoimmune Diseases; Autoimmune Process; Binding Sites; Brain; Cataplexy; Caucasians; Caucasoid Race; Cells; Code; Complex; Disease; Disease Association; Disease susceptibility; Dissociation; Ethnic group; Exons; Genes; Genetic Polymorphism; Goals; HLA Antigens; Haplotypes; Homozygote; Hypothalamic structure; In Vitro; Insulin-Dependent Diabetes Mellitus; Lead; Mediating; Modeling; Mononuclear; Multiple Sclerosis; Narcolepsy; National Institute of Neurological Disorders and Stroke; Neurons; Patients; Peptide T; Phase; Phenotype; Play; Population; Predisposition; Principal Investigator; Promoter Regions; Reporting; Request for Applications; Role; T-Cell Receptor; TCR Activation; Techniques; Titanium; Variant; Work; case control; cost; dimer; high risk; hypocretin; interest; member; nervous system disorder; novel therapeutics; promoter; prototype; public health relevance; tool

DESCRIPTION (provided by applicant): Narcolepsy-cataplexy affects 0.05% of the US population. The cause of the disorder is a loss of hypocretin/orexin neurons in the hypothalamus, of likely autoimmune origin. The disease is uniquely tightly associated with Human Leukocyte Antigen (HLA) DQB1*0602, and may serve as a model to the study of other autoimmune diseases affecting the brain. A weaker association with the T-Cell receptor (TCR) loci is also found. The focus of this application is to sequence the HLA-DQA1 and DQB1 exons and promoter region in 4,000 controls and 3,500 patients with DQB1*0602 like haplotypes. Patients and controls will include Asians, Caucasians and African Americans. The ultimate goal of this project is to determine which DQA1 and DQB1 amino acids are involved in disease susceptibility, and to model the DQ heterodimer binding site involved. Together with work ongoing in the TCR arena, this project offers the opportunity to model the HLA-peptide-TCR trimolecular complex involved in narcolepsy susceptibility. It will also make use of the newly developed FLX 454 titanium sequencing technique to generate and analyze high throughput, low cost full HLA DQA1 and DQB1 sequence, and to develop and perfect new statistical analytic tools, such as the Sequence Variant Type Analysis (SFVT), for disease association studies. PUBLIC HEALTH RELEVANCE (provided by applicant): Narcolepsy affects 1/2000 Americans and is a common neurological disorder. The proposed study may lead to new therapeutic avenues for the disorder.

描述（由申请方提供）：嗜睡症-紧张症影响0.05%的美国人群。这种疾病的原因是下丘脑中下丘脑分泌素/食欲素神经元的丢失，可能是自身免疫性起源。这种疾病与人类白细胞抗原（HLA）DQB 1 *0602密切相关，可以作为研究影响大脑的其他自身免疫性疾病的模型。还发现与T细胞受体（TCR）基因座的相关性较弱。本申请的重点是对4，000名对照和3，500名具有DQB 1 *0602样单倍型的患者的HLA-DQA 1和DQB 1外显子和启动子区域进行测序。患者和对照将包括亚洲人、高加索人和非裔美国人。该项目的最终目标是确定DQA 1和DQB 1氨基酸参与疾病易感性，并模拟DQ异源二聚体结合位点。与TCR竞技场正在进行的工作一起，该项目提供了对涉及嗜睡症易感性的HLA-肽-TCR三分子复合物进行建模的机会。它还将利用新开发的FLX 454钛测序技术生成和分析高通量、低成本的HLA DQA 1和DQB 1全序列，并开发和完善新的统计分析工具，如序列变异类型分析（SFVT），用于疾病关联研究。 公共卫生相关性（由申请人提供）：嗜睡症影响1/2000的美国人，是一种常见的神经系统疾病。这项拟议中的研究可能会为这种疾病带来新的治疗途径。