Spatial mapping of MS genetics on affected brain tissue

1例自身免疫性神经退行性疾病中的多发性硬化症(MS)影响超过2.3 全球200万人，以局限性神经炎为特征，导致 3保护性髓鞘覆盖轴突，最终形成脱髓鞘病变。 4多发性硬化症具有明确而广泛的遗传成分。我们的长期目标是确定 MS遗传学在中枢神经系统疾病发病中的5种作用机制 6系统(CNS)。本应用的总体目标是确定关键的中枢神经系统细胞。 7研究了遗传关联和各自的机制。中心假设是各种不同的 8个中枢神经系统细胞受疾病遗传学影响，其空间分布反映了潜在的 9病变形成机制。这一假设是基于初步结果提出的 10在分布在MS病变周围的不同细胞中发现了MS遗传学的明显激活。 11这项拟议研究的基本原理是，这些中枢神经系统细胞及其SpA的发现- 12个基因的分布，将有助于更好地理解基因对疾病的贡献。 13发展和进展，并提供一份具有高度细胞特异性的潜在新药靶点清单。 14为了检验假设和实现总体目标，以下具体目标是有利的- 15提出：(I)确定在受影响的多发性硬化症中富含疾病相关遗传学的细胞 16岁的大脑。我们将从In-Seq的三个区域同时产生单细胞RNA-seq/ATAC-seq 17例活动期和非活动期多发性硬化症病变的感兴趣区(ROI)，以及高场磁共振成像后的对照脑。我们 18将把这些数据与最新的MS遗传学相结合，以识别丰富的中枢神经系统细胞， 19它们的空间分布和潜在机制。最后，我们将验证这些发现-- 20项全基因组空间转录组学技术。

1 Multiple Sclerosis (MS) in an autoimmune neurodegenerative disease affecting more than 2.3 2 million people worldwide, characterized by localized neuroinflammation leading to loss of the 3 protective myelin sheath covering axons and eventually the formation of demyelinated lesions. 4 MS has a well-defined and extensive genetic component. Our long-term goal is to identify the 5 mechanisms via which MS genetics contribute to disease pathogenesis in the central nervous 6 system (CNS). The overall objective in this application, is to determine key CNS cells that medi- 7 ate genetic associations and respective mechanisms. The central hypothesis is that various 8 CNS cells are affected by the disease genetics and their spatial distribution reflects underlying 9 mechanisms of lesion formation. This hypothesis is formulated based on preliminary results that 10 identified a distinct activation of MS genetics in different cells distributed around MS lesions. 11 The rationale for the proposed research is that the discovery of these CNS cells, and their spa- 12 tial distribution, will lead to a better understanding of the genetic contribution to the disease de- 13 velopment and progression and provide a highly cell-specific list of potential new drug targets. 14 To test the hypothesis and achieve the overall objective, the following specific aims are pro- 15 posed: (i) Identify the cells that are enriched for disease-associated genetics in the affected MS 16 brain. We will generate simultaneously single cell RNA-seq/ATAC-seq from three regions of in- 17 terest (ROIs) of active and inactive MS lesions and control brains, following high-field MRI. We 18 will integrate these data with the most recent MS genetics in order to identify enriched CNS cell, 19 their spatial distribution, and underlying mechanisms. Finally, we will validate these findings uti- 20 lizing genome-wide spatial transcriptomics technologies.