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

多发性硬化症脑损伤的高空间分辨率多组学测序

• 批准号: 10725223
• 负责人: Yanxiang Deng
• 金额: $ 47.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725223
• 关键词: 3-Dimensional; Address; Affect; Area; Bar Codes; Biochemistry; Biological Markers; Biology; Brain; CNS autoimmune disease; Cell Nucleus; Cells; Characteristics; Chromatin; Coupled; Data; Degenerative Disorder; Demyelinations; Development; Disease; Dissociation; Environment; Genetic Transcription; Genomics; Heterogeneity; Human; Immune; Immune Targeting; Immune response; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Lesion; Longevity; Maps; Mentorship; Messenger RNA; Methods; Microfluidics; Modality; Molecular; Molecular Profiling; Motivation; Multiple Sclerosis; Multiple Sclerosis Lesions; Neighborhoods; Neuroglia; Neurologic; Outcome; Peripheral; Persons; Phenotype; Postdoctoral Fellow; Process; Progressive Disease; Proteins; Refractory; Relapse; Research; Resolution; Sampling; Scheme; Shapes; Suspensions; Technology; Testing; Time; Tissues; Work; axon injury; biological systems; brain cell; brain tissue; cell type; epigenomics; gene regulatory network; healthspan; histone modification; immune cell infiltrate; improved; microdevice; multiple omics; neuroinflammation; neuron loss; novel; novel therapeutic intervention; repaired; success; targeted treatment; tool; trafficking; transcriptome; white matter

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.

项目概要 多发性硬化症（MS）是一种中枢神经系统的神经炎症性自身免疫性疾病，会导致脱髓鞘， 轴突损伤和神经元损失。涉及外周激活物质运输的异常免疫反应 进入中枢神经系统的免疫细胞是复发性多发性硬化症中炎症性疾病活动的主要驱动因素， 免疫靶向疗法的成功凸显了这一点。相比之下，不复发的生物学 进行性疾病被认为涉及中枢神经系统区室化炎症和退行性疾病 机制仍然更难治疗，部分原因是基因调控网络的复杂性 与多发性硬化症病变进展的细胞类型特异性机制相结合。细胞有哪些类型或亚型 受此过程及其在组织环境中的空间异质性以及这些细胞如何影响的影响 对组织环境仍然知之甚少，这阻碍了针对目标的策略的制定 这些细胞可以改善健康/寿命或利用这些细胞或分泌因子来促进组织 改造和修复，凸显了对绘制细胞和周围环境的工具的迫切需求 组织病变并生成生物标志物来定义空间和表型异质性。该项目旨在 结合新颖的分子条形码方案和下游生物化学 用于空间多组学的微型设备，允许同时分析多种表观基因组模式、整体 转录组，以及以空间分辨方式在组织尺度和细胞水平上的一组蛋白质。我们将 应用空间多组学绘制从脱髓鞘白质边缘解剖的人脑组织图 MS炎症不同阶段的病变以及脱髓鞘病变核心、白质 来自神经健康大脑的斑块周围和正常白质。空间组学数据将与 单细胞数据来识别不同受影响细胞的特征并执行组织邻域分析 定义多发性硬化症病变中的细胞组成和分子特征。预期成果及主要内容 贡献包括：（1）关于不同细胞类型及其表观基因组、转录的基础知识 MS 脑损伤 3D 组织组织背景下的表型（蛋白质）特征和（2） 提供了测试当前批准的治疗方案未针对的多发性硬化症新治疗方法的可能性 治疗。由此产生的数据将有助于更好地理解组织组织之间的关系， MS 中的功能和基因调控网络。