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

基本信息

批准号：
8259851
负责人：
Emmanuel J Mignot
金额：
$ 38.07万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8259851
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 Role T-Cell Receptor TCR Activation Techniques Titania Titanium Variant Work case control cost dimer high risk hypocretin interest member nervous system disorder novel therapeutics promoter prototype public health relevance tool

项目摘要

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（由申请人提供）： 0.05% 的美国人口患有嗜睡症猝倒症。该疾病的原因是下丘脑中下丘脑分泌素/食欲素神经元的丧失，可能是自身免疫性疾病所致。该疾病与人类白细胞抗原 (HLA) DQB1*0602 密切相关，可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) 位点的关联较弱。此应用的重点是对 4,000 名对照者和 3,500 名具有 DQB1*0602 样单倍型的患者的 HLA-DQA1 和 DQB1 外显子和启动子区域进行测序。患者和对照将包括亚洲人、白人和非裔美国人。该项目的最终目标是确定哪些 DQA1 和 DQB1 氨基酸与疾病易感性有关，并对所涉及的 DQ 异二聚体结合位点进行建模。与 TCR 领域正在进行的工作一起，该项目提供了对与嗜睡症易感性相关的 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钛测序技术来生成和分析高通量、低成本的全HLA DQA1和DQB1序列，并开发和完善新的统计分析工具，例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）：发作性睡病影响着 1/2000 的美国人，是一种常见的神经系统疾病。拟议的研究可能会为这种疾病带来新的治疗途径。