Spatial mapping of MS genetics on affected brain tissue

受影响脑组织的多发性硬化症遗传学空间图谱

• 批准号: 10577900
• 负责人: TANUJA CHITNIS
• 金额: $ 21.99万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577900
• 关键词: ATAC-seq; Affect; Area; Autoimmune; Autopsy; Axon; Biological Assay; Biology; Brain; Cell Communication; Cell Nucleus; Cells; Central Nervous System; Chromatin; Chromosome Mapping; Data; Demyelinations; Development; Disease; Dissection; Drug Targeting; Genes; Genetic; Genetic Diseases; Goals; Heritability; Human; Immune; Inflammatory; Lesion; Link; Magnetic Resonance Imaging; Maps; Mediating; Microglia; Mission; Molecular; Multiomic Data; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin Sheath; Neurodegenerative Disorders; Organ; Outcome; Pathogenesis; Pathology; Peripheral; Persons; Positioning Attribute; Procedures; Protocols documentation; Public Health; Reporting; Research; Selection for Treatments; Spatial Distribution; Technology; Testing; Tissue Sample; Tissues; Translating; Translations; United States National Institutes of Health; brain tissue; causal variant; cell type; data integration; diagnostic strategy; diagnostic tool; disability; drug development; genetic association; genetic variant; genome wide association study; genome-wide; genomic data; insight; interest; mind control; neuroinflammation; new therapeutic target; novel therapeutics; precision medicine; preservation; single nucleus RNA-sequencing; single-cell RNA sequencing; stem cells; transcriptomics; white matter

Multiple Sclerosis (MS) in an autoimmune neurodegenerative disease affecting more than 2.3 million people worldwide, characterized by localized neuroinflammation leading to loss of the protective myelin sheath covering axons and eventually the formation of demyelinated lesions. MS has a well-defined and extensive genetic component. Our long-term goal is to identify the mechanisms via which MS genetics contribute to disease pathogenesis in the central nervous system (CNS). The overall objective in this application, is to determine key CNS cells that medi-ate genetic associations and respective mechanisms. The central hypothesis is that various CNS cells are affected by the disease genetics and their spatial distribution reflects underlying mechanisms of lesion formation. This hypothesis is formulated based on preliminary results that identified a distinct activation of MS genetics in different cells distributed around MS lesions. The rationale for the proposed research is that the discovery of these CNS cells, and their spa-tial distribution, will lead to a better understanding of the genetic contribution to the disease de-velopment and progression and provide a highly cell-specific list of potential new drug targets. To test the hypothesis and achieve the overall objective, the following specific aims are pro-posed: (i) Identify the cells that are enriched for disease-associated genetics in the affected MS brain. We will generate simultaneously single cell RNA-seq/ATAC-seq from three regions of in-terest (ROIs) of active and inactive MS lesions and control brains, following high-field MRI. We will integrate these data with the most recent MS genetics in order to identify enriched CNS cell, their spatial distribution, and underlying mechanisms. Finally, we will validate these findings uti-lizing genome-wide spatial transcriptomics technologies.

多发性硬化症（MS）是一种自身免疫性神经退行性疾病，影响全球230多万人，其特征是局部神经炎症，导致覆盖轴突的保护性髓鞘丢失，最终形成脱髓鞘病变。MS具有明确的和广泛的遗传成分。我们的长期目标是确定MS遗传学对中枢神经系统（CNS）疾病发病机制的作用机制。本申请的总体目标是确定介导遗传关联和各自机制的关键CNS细胞。中心假设是各种CNS细胞受疾病遗传学的影响，它们的空间分布反映了病变形成的潜在机制。这一假设是基于初步结果制定的，这些结果确定了MS病变周围分布的不同细胞中MS遗传学的不同激活。提出这项研究的理由是，这些CNS细胞的发现及其空间分布将有助于更好地了解遗传对疾病发展和进展的贡献，并提供一个高度细胞特异性的潜在新药靶点清单。为了检验该假设并实现总体目标，提出了以下具体目标：（i）鉴定受影响的MS脑中富集疾病相关遗传学的细胞。在高场MRI之后，我们将从活动性和非活动性MS病变和对照大脑的三个感兴趣区域（ROI）同时生成单细胞RNA-seq/ATAC-seq。我们将这些数据与最新的MS遗传学相结合，以鉴定富集的CNS细胞， 其空间分布和潜在机制。最后，我们将利用全基因组空间转录组学技术验证这些发现。