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手型细胞免疫球蛋白的作用 神经系统疾病中的受体（KIR）基因座。该项目作为较大的关键组成部分提交 靛蓝（神经疾病工作组的免疫生殖学）努力。这个国际 协作以驾驶原则为基础，即通过协作和协同作用，我们将共同进行 旨在理解神经炎症和神经退行性的遗传原因的快速发展。 使用现代测序方法和艺术生物信息学和分析的状态，项目2的目的是 为了建立和完善KIR遗传多态性与多发性硬化症的关联，肌无力，肌无力 神经霉素炎，帕金森氏病和精神分裂症。免疫学的核心，至关重要 人类健康，KIR分子及其人类白细胞抗原（HLA）配体由复杂编码 具有极高水平序列和结构变异和复杂表达的遗传系统 模式。基于校长和共同研究人员以及其他人的工作，并在发现 KIR和HLA等位基因与感染性，自身免疫性疾病，移植的组合关联 结果和怀孕，免疫基因组研究领域现在正在荧光。但是，迄今的研究 中枢神经系统疾病中的KIR很少，并且仅限于非常低的分辨率基因分型。 与项目1协同作用，该项目侧重于同一同龄人的HLA的变化，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在IN中的相互作用 神经疾病。在拟议的工作中，我们将表征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基因分型实现的变化 并应用于一系列既定且特征良好的人群的尺寸和多样性 关于疾病，表型和种族。在高分辨率下的KIR变异表征将允许 我们充分理解这种多样性在广泛的神经疾病中的影响。我们将利用 我们在临床神经科学，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，耦合 使用最先进的实验室方法论，以提高我们对KIR在神经学中的作用的理解 疾病。