Spatial mapping of MS genetics on affected brain tissue

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。多发性硬化症具有定义明确和广泛的遗传成分。我们的长期目标是确定MS遗传学在中枢神经系统(CNS)疾病发病机制中的作用机制。这项应用的总体目标是确定参与遗传关联和各自机制的关键中枢神经系统细胞。中心假设是各种中枢神经系统细胞受到疾病遗传学的影响，它们的空间分布反映了病变形成的潜在机制。这一假说是基于初步结果提出的，这些结果确认了分布在MS病变周围的不同细胞中MS遗传学的明显激活。这项拟议研究的基本原理是，这些中枢神经系统细胞的发现及其空间分布将有助于更好地理解基因对疾病发生和发展的贡献，并提供潜在新药靶点的高度细胞特异性清单。为了验证这一假设并实现总体目标，提出了以下具体目标：(I)在受影响的多发性硬化症大脑中鉴定富含疾病相关遗传学的细胞。我们将在高场MRI后，同时从活动期和非活动期MS病变的三个感兴趣区(ROI)和对照脑中产生单细胞RNA-seq/ATAC-seq。我们将把这些数据与最新的MS遗传学相结合，以鉴定丰富的中枢神经系统细胞， 它们的空间分布和潜在的机制。最后，我们将利用全基因组空间转录技术来验证这些发现。

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.