KIR association studies in neurological diseases

神经系统疾病中的 KIR 关联研究

• 批准号: 9335468
• 负责人: Marcelo Fernandez-Vina
• 金额: $ 29.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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/9335468
• 关键词: Address; Affect; African American; Alleles; Antigenic Variation; Asians; Autoimmune Diseases; Automobile Driving; Base Sequence; Binding; Bioinformatics; Biological Markers; Central Nervous System Diseases; Clinical; Collaborations; Complex; Coupled; Data; Epitopes; Ethnic Origin; European; Extracellular Domain; Genetic; Genetic Polymorphism; Genotype; Goals; HLA Antigens; Health; Hispanics; Human; Immune System Diseases; Immune System and Related Disorders; Immunity; Immunogenetics; Immunoglobulins; Immunology; Individual; Influentials; International; Killer Cells; Laboratories; Ligands; Link; Linkage Disequilibrium; Mediating; Methodology; Methods; Modernization; Multiple Sclerosis; Myasthenia Gravis; NK Cell Activation; Natural Killer Cells; Nature; Nerve Degeneration; Neuromyelitis Optica; Neurosciences; Outcome; Parkinson Disease; Pathogenesis; Patients; Pattern; Peptides; Population Group; Pregnancy; Promoter Regions; Property; Protocols documentation; Research; Research Personnel; Resolution; Role; Sample Size; Sampling; Schizophrenia; Specificity; Statistical Data Interpretation; Surface; System; Transplantation; Variant; Work; antigen binding; cohort; combinatorial; data management; data resource; disease phenotype; disorder risk; experience; genetic association; human leukocyte antigen testing; improved; innovation; nervous system disorder; neuroinflammation; next generation sequencing; novel; pleiotropism; promoter; receptor; sample collection; synergism; working group

The overall goal of this project is to fully describe and characterize the role of the Killer-cell Immunoglobulinlike Receptor (KIR) loci in neurological disease. This project is submitted as a key component of the larger INDIGO (Immunogenetics of Neurological DIseases working GrOup) consortium effort. This international collaboration builds on the driving principle that through collaboration and synergy, collectively we will make rapid progress towards understanding the genetic causes of neuroinflammation and neurodegeneration. Using modern sequencing methods and state of the art bioinformatics and analytics, the purpose of Project 2 is to establish and refine the association of KIR genetic polymorphism with multiple sclerosis, myasthenia gravis, neuromyelitis optica, Parkinson’s disease and schizophrenia. Central to immunity and critically important for human health, KIR molecules and their Human Leukocyte Antigen (HLA) ligands are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. Building on the work by the principal and co-investigators and others, and fueled by the discovery of combinatorial associations of KIR and HLA alleles with infectious, autoimmune diseases, transplantation outcome and pregnancy, the field of immunogenomic research is now flourishing. However, studies to-date of KIR in diseases of the central nervous system have been few and limited to very low resolution genotyping. Synergized with Project 1, which focuses on variation of HLA in the same cohorts, this project will ascertain the impact of KIR variation, including promoter region polymorphism, and the interaction of KIR with HLA in neurological disease. In the proposed work we will characterize the nature and extent of the association of KIR variation achieved via high-throughput, high-resolution Next-Generation Sequencing (NGS) KIR genotyping and applied across a set of established and well-characterized cohorts of unprecedented size and diversity with respect to disease, phenotype and ethnicity. Characterization of KIR variation at high resolution will permit us to fully appreciate the impact of this diversity across a wide range of neurological diseases. We will leverage the extensive available experience within our consortium in clinical neuroscience, immunogenetics, and immunology, with sophisticated data management, bioinformatics, and statistical analysis expertise, coupled with state of the art laboratory methodology to improve our understanding of the role of KIR in neurological disease.

该项目的总体目标是充分描述和表征杀伤细胞免疫球蛋白样的作用 神经系统疾病中的受体 (KIR) 位点作为更大项目的关键组成部分提交。 INDIGO（神经疾病免疫遗传学工作组）这是国际联盟的努力。 合作建立在这样的驱动原则之上：通过合作和协同，我们将共同创造 对神经炎症和神经退行性变的遗传原因的理解取得了快速进展。 使用现代测序方法和最先进的生物信息学和分析，项目 2 的目的是 建立并完善 KIR 基因多态性与多发性硬化症、重症肌无力、 视神经脊髓炎、帕金森病和精神分裂症对于免疫至关重要。 人类健康，KIR 分子及其人类白细胞抗原 (HLA) 配体由复杂的编码 具有极高水平的序列和结构变异以及复杂表达的遗传系统 模式以主要研究人员和共同研究人员以及其他人的工作为基础，并受到以下发现的推动。 KIR 和 HLA 等位基因与传染病、自身免疫性疾病、移植的组合关联 然而，迄今为止，免疫基因组学研究领域正在蓬勃发展。 中枢神经系统疾病中的 KIR 很少，并且仅限于非常低分辨率的基因分型。 与项目 1 相结合，该项目侧重于同一队列中 HLA 的变异，该项目将确定 KIR 变异的影响，包括启动子区域多态性，以及 KIR 与 HLA 的相互作用 在拟议的工作中，我们将描述 KIR 关联的性质和程度。 通过高通量、高分辨率下一代测序 (NGS) KIR 基因分型实现变异 并应用于一组规模和多样性前所未有的既定且特征鲜明的群体 就疾病、表型和种族而言，KIR 变异的高分辨率表征将成为可能。 我们将充分认识这种多样性对多种神经系统疾病的影响。 我们联盟在临床神经科学、免疫遗传学和 免疫学，具有复杂的数据管理、生物信息学和统计分析专业知识，结合 采用最先进的实验室方法来提高我们对 KIR 在神经病学中的作用的理解 疾病。