Role of Natural Killer Cell Diversity in Multiple Sclerosis Risk and Disease Course

自然杀伤细胞多样性在多发性硬化症风险和疾病过程中的作用

• 批准号: 10707310
• 负责人: JILL Allison HOLLENBACH
• 金额: $ 76.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707310
• 关键词: African American; Alleles; Biological Assay; CRISPR interference; CRISPR-mediated transcriptional activation; CRISPR/Cas technology; Cell Therapy; Cell physiology; Cellular biology; Chromosome 12; Chromosome 19; Clinical; Complex; Cytometry; Data; Dimensions; Disease; Disease Progression; Disease remission; European ancestry; Future; Genomic Segment; Genomics; Genotype; Goals; Hispanic ancestry; Immunoglobulins; In Vitro; Individual; Investigation; Killer Cells; Leukocytes; Ligands; Longitudinal cohort; Magnetic Resonance Imaging; Maps; Mediating; Methodology; Methods; Modality; Multiple Sclerosis; Natural Killer Cells; Nature; Pathogenesis; Pattern; Phenotype; Predisposition; Receptor Cell; Relapse; Resolution; Risk; Role; Surface; System; Technology; Test Result; Therapeutic; Variant; Work; clinical application; cohort; cytotoxicity; experimental study; genomic data; genomic variation; inducible gene expression; insight; knock-down; multiple sclerosis patient; next generation sequencing; novel; patient population; peripheral blood; phenotypic data; receptor; receptor expression

Project Summary The goal of this project is to comprehensively characterize the role of polymorphic natural killer (NK) cell receptors in multiple sclerosis (MS). Substantial data implicate NK cells in MS pathogenesis, but their precise function in mediating risk and disease course is poorly understood. Given that a large and diverse set of highly variable receptors govern NK cell activity, their characterization in MS promises to yield important insights into the role of NK cells in disease. Thus, we will characterize the nature and extent of the association of genomic variation of NK receptors across a set of diverse, established and deeply phenotyped MS cohorts. This goal will be achieved via our novel high-throughput, high-resolution next-generation sequencing (NGS) methodology. Using state-of-art technologies, we will contextualize this genomic variation by considering NK cell phenotype in disease. Finally, we will explore the functional implications of the observed NK receptor variation, allowing a mechanistic explanation of the impact of NK receptor expression to more fully understand the role of these highly variable receptors in MS. Together, the leukocyte receptor complex (LRC) on chromosome 19 and the natural killer complex (NKC) on chromosome 12 encode more than 90 distinct NK cell receptors, including the extremely polymorphic KIR (killer-cell immunoglobulin-like receptor) and LILR (leukocyte immunoglobulin-like receptors). In the work described here, we approach these complex systems across several key modalities, examining genomic, phenotypic and functional variation of NK receptors in MS to provide the first comprehensive depiction of the role of NK receptors in disease. Our preliminary work in a cohort of European ancestry identified a significant association of KIR variation with risk for developing MS, as well as with clinical and MRI features of disease. In Specific Aim 1, we will extend these findings to diverse patient populations and characterize KIR variation in MS across ancestries, in an additional cohort with longitudinal clinical and MRI data, and by investigating genomic variation of all known polymorphic NK receptors and their corresponding ligands. In Specific Aim 2, we will more fully resolve the role of these receptors in disease course by examining temporal expression patterns of NK cell receptors in individuals with MS through longitudinal CyTOF analysis. Finally, in Specific Aim 3, we will contextualize these results by harnessing CRISPR technology to characterize the impact of NK cell receptor expression level on NK cell function. This work promises to fill critical gaps in our understanding of the role of NK cells in MS. Because NK cell activity is tightly governed by the highly variable receptors that we investigate in this proposal, this work will provide important insight into the regulatory mechanisms underlying the influence of NK cells in MS susceptibility and disease course. The results will bear both on our understanding of disease pathogenesis and future efforts to develop NK cell-based therapeutic options.

项目概要 该项目的目标是全面表征多态性自然杀伤（NK）细胞的作用 多发性硬化症 (MS) 中的受体。大量数据表明 NK 细胞参与 MS 发病机制，但其精确性 人们对调节风险和疾病过程的功能知之甚少。鉴于大量且多样化的高度 可变受体控制 NK 细胞活性，它们在 MS 中的表征有望产生重要的见解 NK 细胞在疾病中的作用。因此，我们将描述基因组关联的性质和程度 NK 受体在一组不同的、已建立的和深度表型的 MS 群体中的变异。这个目标将 通过我们新颖的高通量、高分辨率下一代测序 (NGS) 方法来实现。 使用最先进的技术，我们将通过考虑 NK 细胞表型来了解这种基因组变异 疾病。最后，我们将探讨观察到的 NK 受体变异的功能含义，从而允许 NK 受体表达影响的机制解释，以更充分地理解这​​些高度的作用 MS 中的可变受体。 19 号染色体上的白细胞受体复合物 (LRC) 和天然 12 号染色体上的杀伤复合物 (NKC) 编码 90 多种不同的 NK 细胞受体，包括极其 多态性 KIR（杀伤细胞免疫球蛋白样受体）和 LILR（白细胞免疫球蛋白样受体）。 在这里描述的工作中，我们通过几种关键方式处理这些复杂的系统，检查 MS 中 NK 受体的基因组、表型和功能变异提供了第一个全面的描述 NK 受体在疾病中的作用。我们对一群欧洲血统的初步研究确定了 KIR 变异与发生 MS 的风险以及与 MS 的临床和 MRI 特征显着相关 疾病。在具体目标 1 中，我们将这些发现扩展到不同的患者群体并描述 KIR 的特征 在具有纵向临床和 MRI 数据的附加队列中，不同祖先的 MS 差异 研究所有已知多态性 NK 受体及其相应配体的基因组变异。在 具体目标2，我们将通过检查时间来更全面地解析这些受体在疾病过程中的作用 通过纵向 CyTOF 分析了解 MS 个体中 NK 细胞受体的表达模式。最后，在 具体目标 3，我们将利用 CRISPR 技术来描述这些结果的影响特征 NK 细胞受体表达水平对 NK 细胞功能的影响。这项工作有望填补我们的关键空白 了解 NK 细胞在 MS 中的作用。因为 NK 细胞的活性受到高度可变的因素的严格控制 我们在本提案中研究的受体，这项工作将为监管提供重要的见解 NK 细胞影响 MS 易感性和病程的潜在机制。结果将承担 既基于我们对疾病发病机制的理解，也基于未来开发基于 NK 细胞的治疗方法的努力 选项。