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.

项目摘要 多发性硬化症（MS）是CNS的神经炎症自身免疫性疾病，导致脱髓鞘， 轴突损伤和神经元丧失。异常免疫反应，涉及贩运周围激活的免疫反应 免疫细胞进入中枢神经系统是复发多发性硬化症的炎性疾病活性的主要驱动因素，因为 受免疫靶向疗法的成功强调。相比之下，非竞争的生物学 据认为进行性疾病涉及中枢神经系统的炎症和退化性疾病 机制（仍然对治疗更难治性），部分原因是基因调节网络的复杂性 结合MS病变进展的细胞类型特异性机制。细胞的哪种类型或亚型是 受此过程的影响及其在组织环境中的空间异质性以及这些细胞如何影响 组织环境的理解仍然很少，这排除了针对目标的策略 这些细胞改善健康范围/寿命或利用这些细胞或分泌因素以促进组织 重塑和维修，突出了对映射单元格和周围环境的工具的紧迫需求 组织病变并产生生物标志物来定义空间和表型异质性。这个项目旨在 开发新颖的分子条形码方案和下游生物化学与新颖 用于空间多摩管的微型发行版，允许同时分析多表观基因组模态，整个 转录组和以空间分辨方式在组织尺度和细胞水平上的蛋白质面板。我们将 将空间多摩学应用于绘制从脱髓鞘白质边缘解剖的人脑组织 MS病变在不同炎症阶段以及脱髓鞘病变核心（白质） 神经学健康的大脑的periplaque和正常的白质。空间轨迹数据将与 单细胞数据以识别不同受影响细胞的特征，并执行组织邻居分析 定义MS病变中的细胞组成和分子特征。预期的结果和专业 贡献包括：（1）有关各种细胞类型及其表观基因组的基本知识 在MS脑病变中3D组织组织的背景下的表型（蛋白质）特征和（2） 提供为MS测试新的治疗方法的可能性 治疗。由此产生的数据将使您对组织组织之间的关系有更好的了解， MS中的功能和基因调节网络。