Immunogenetic Determinants of Disease Risk in Neurological Disease

神经系统疾病风险的免疫遗传学决定因素

基本信息

批准号：
8955877
负责人：
Marcelo Fernandez-Vina
金额：
$ 141.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8955877
关键词：
6p21 Address Algorithms Alleles Automobile Driving Bioinformatics Biological Cataloging Catalogs Central Nervous System Diseases Clinical Collaborations Complex DNA Data Data Set Development Dideoxy Chain Termination DNA Sequencing Disease Disease susceptibility Elements Genes Genetic Genetic Polymorphism Genetic Risk Genomics Genotype Goals Gold Grant HLA-A gene Haplotypes Health Human Human Genome Immunity Immunogenetics Inflammatory Inherited International Investments Knowledge Laboratories Leadership Logistics Major Histocompatibility Complex Maps Mediating Medical Genetics Methodology Methods Molecular Multiple Sclerosis Myasthenia Gravis Nerve Degeneration Neuromyelitis Optica Overlapping Genes Parkinson Disease Participant Pathway interactions Patients Pattern Predisposition Productivity Publishing Research Research Design Research Infrastructure Resolution Risk Sampling Schizophrenia Scientist Signal Transduction Single Nucleotide Polymorphism Site Surveys System Technology Variant analytical method base central nervous system injury cost effective data management design disorder risk genetic analysis genetic association genome wide association study genotyping technology innovation insight nervous system disorder neurogenetics neuroinflammation neuropsychiatry next generation sequencing novel pleiotropism programs promoter public health relevance response sample collection screening skills tool trait working group

项目摘要

DESCRIPTION (provided by applicant): This project, submitted as a multi-center U19 application on behalf of the Immunogenetics of Neurological Diseases working GrOup (INDIGO), has as its primary goal to identify and characterize the repertoire of HLA and KIR genes and alleles that predispose to neurological diseases. WE focus the effort on multiple sclerosis, neuromyelitis optica, myasthenia gravis, Parkinson's disease, and schizophrenia - all diseases with established association signals in the Major Histocompatibility Complex (MHC). To achieve our goals, we have assembled a multi-disciplinary international team that brings together complementary expertise (immuno- and neuro-genetics, clinical, and computational) and a remarkable track record of productivity to carry out a study of broad scope and depth. Through this collaboration, we will leverage rich and informative datasets exceeding 15,000 study participants (cases) and connect genetics with CNS disease utilizing advanced molecular and bio-informatics tools. The study design includes 2 independent, yet interactive Projects supported by a common administrative and data/sample management infrastructure. Project 1 proposes a comprehensive sequence variation screening in nine HLA loci and association analysis with disease risk. Project 2 will assess the distribution of KIR-associated variants, KIR copy number, and KIR promoter polymorphisms in the same diseases. Both projects will take advantage of the ancestral diversity of the datasets to advance the fine mappings of the discovered associations. Naturally, we will also pursue the analysis of HLA-KIR interactions vis-à-vis disease susceptibility. Genetic pleiotropy and the identification of common immunogenetics across diseases are additional important elements of this initiative. The overarching goal of this project is to achieve a productive integration of molecular and clinical datasets to elucidate the genetic pathways that drive risk to CNS injury and neurodegeneration. The isolation of definite HLA- KIR associations with the risk of neuroinflammation and neurodegeneration could be transformative by revealing fundamental insights about primary disease mechanisms.

描述（由应用程序提供）：该项目是代表神经系统疾病工作组（INDIGO）的免疫原料（INDIGO）作为多中心U19应用程序提交的，其主要目标是识别和表征HLA和KIR基因和等位基因的曲目。我们将精力集中在多发性硬化症，神经瘤性炎，肌无力，肌无力，帕金森氏病和精神分裂症 - 所有疾病中均具有在主要组织相容性复合物（MHC）中具有既定关联信号的疾病。为了实现我们的目标，我们组建了一个多学科的国际团队，该团队汇集了互补的专业知识（免疫和神经基因，临床和计算），并具有出色的生产力记录，以进行广泛的范围和深度研究。通过这种合作，我们将利用高级分子和生物信息学工具来利用超过15,000名研究参与者（案例）的丰富和信息丰富的数据集，并将遗传学与中枢神经系统疾病联系起来。研究设计包括2个独立但互动的项目，这些项目由共同的行政和数据/样本管理基础架构支持。项目1提出，在九个HLA基因座和与疾病风险的关联分析中进行了全面的序列变化筛查。项目2将评估相同疾病中KIR相关变体，KIR拷贝数和KIR启动子多态性的分布。这两个项目都将利用数据集的祖先多样性，以推动发现协会的精细映射。自然，我们还将对疾病易感性进行HLA-KIR相互作用的分析。遗传性多效性和跨疾病的常见免疫遗传学的鉴定是该倡议的其他重要因素。该项目的总体目标是实现分子和临床数据集的产物整合，以阐明将CNS损伤和神经变性风险带来风险的遗传途径。通过揭示有关主要疾病机制的基本见解，可以通过神经炎症和神经变性的风险进行定义的Hlakir关联分离。