High-spatial-resolution multi-omics sequencing of brain lesions in multiple sclerosis

项目摘要 多发性硬化症(MS)是一种中枢神经系统炎症性自身免疫性疾病，导致脱髓鞘， 轴突损伤和神经元丢失。涉及外周激活的运输的异常免疫反应 免疫细胞进入中枢神经系统是复发性多发性硬化症炎症性疾病活动的主要驱动力，AS 免疫靶向治疗的成功凸显了这一点。相比之下，不复发的生物学 进行性疾病被认为与中枢神经系统分区炎症和退行性疾病有关。 机制，这仍然是更难治疗，部分原因是基因调控网络的复杂性 再加上MS病变进展的细胞类型特异性机制。什么类型或子类型的单元格 受这一过程的影响以及它们在组织环境中的空间异质性以及这些细胞如何影响 组织环境仍然知之甚少，这排除了制定靶向策略的可能性。 这些细胞可以延长健康寿命或利用这些细胞或分泌因子来促进组织 重建和修复，突显出迫切需要工具来绘制细胞和周围环境的地图 组织损伤并产生生物标记物来定义空间和表型的异质性。该项目旨在 开发新的分子条码方案和下游生物化学与新的 用于空间多组学的微装置，允许同时分析多个表观基因组模式，整体 转录组，以及以空间分辨方式在组织和细胞水平上的一组蛋白质。我们会 空间多组学在人脑脱髓鞘白质边缘组织定位中的应用 MS病变在炎症的不同阶段以及脱髓鞘病变的核心、白质 周围斑块和正常脑白质来自神经学健康的大脑。空间组学数据将与 单细胞数据以识别不同受影响细胞的特征并执行组织邻域分析以 明确MS病变中的细胞成分和分子特征。预期结果和主要结果 贡献包括：(1)关于不同细胞类型及其表观基因组、转录的基本知识 以及MS脑部病变中3D组织背景下的表型(蛋白质)特征和(2) 提供测试当前批准的未针对多发性硬化症的新治疗方法的可能性 治疗。所得到的数据将导致更好地理解组织组织之间的关系， 功能，以及MS中的基因调控网络。

Project Summary Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease of the CNS that results in demyelination, axonal injury, and neuronal loss. Abnormal immune responses involving the trafficking of peripherally activated immune cells into the CNS are major drivers of inflammatory disease activity in relapsing multiple sclerosis, as underscored by the success of immune-targeting therapies. By contrast, the biology of non-relapsing progressive disease is thought to involve CNS-compartmentalized inflammation and degenerative disease mechanisms, which remains more refractory to therapy, due in part to the complexity of gene regulatory network coupled with cell-type-specific mechanisms of MS lesion progression. What types or subtypes of cells are affected by this process and their spatial heterogeneity in the tissue context as well as how these cells impact the tissue environments remain poorly understood, which precludes the development of strategies to target these cells to improve healthspan/lifespan or harnessing these cells or secreted factors to promote tissue remodeling and repair, highlighting a pressing need for tools to map cells and the surround environments in the tissues lesion and generate biomarkers to define spatial and phenotypic heterogeneity. This project aims to develop novel molecular barcoding scheme and downstream biochemistry in combination with novel microdevices for spatial multi-omics that allows simultaneous profiling of multi epigenomic modalities, whole transcriptome, and a panel of proteins at tissue scale and cellular level in a spatially resolved manner. We will apply the spatial multi-omics to map human brain tissue dissected from the edge of demyelinated white matter MS lesions at different stages of inflammation as well as the demyelinated lesion core, the white matter periplaque and normal white matter from neurologically healthy brains. Spatial omics data will be integrated with single-cell data to identify signatures of different affected cells and perform the tissue neighborhood analysis to define the cellular composition and molecular signatures in MS lesions. The expected outcomes and the major contributions include: (1) Fundamental knowledge on diverse cell types and their epigenomic, transcriptional and phenotypic (protein) characteristics in the context of 3D tissue organization in the MS brain lesions and (2) Offer the possibility of testing new therapeutic approaches for MS that are not targeted by currently approved treatments. The resulting data will lead to a better understanding of the relationship between tissue organization, function, and gene regulatory networks in MS.