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）是一种导致脱髓鞘的CNS神经炎性自身免疫性疾病， 轴突损伤和神经元损失。异常免疫反应涉及外周活化的 免疫细胞进入中枢神经系统是复发性多发性硬化症中炎性疾病活动的主要驱动因素， 免疫靶向疗法的成功强调了这一点。相比之下， 进行性疾病被认为涉及CNS区室化炎症和退行性疾病 部分由于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。什么类型或亚型的细胞是 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，这阻碍了针对 这些细胞来改善健康/寿命或利用这些细胞或分泌的因子来促进组织 重塑和修复，突出了对工具的迫切需要，以映射细胞和周围环境中的 组织损伤并产生生物标志物以定义空间和表型异质性。该项目旨在 开发新的分子条形码方案和下游生物化学， 用于空间多组学的微器件，其允许同时分析多个表观基因组模式、整个 转录组和一组蛋白质在组织规模和细胞水平上以空间分辨的方式。我们将 应用空间多组学对从脱髓鞘的白色物质的边缘解剖的人脑组织进行映射 不同炎症阶段的MS病变以及脱髓鞘病变核心、白色物质 斑块周围和正常白色物质。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，并进行组织邻域分析， 定义MS病变中的细胞组成和分子特征。预期成果和主要 贡献包括：（1）关于不同细胞类型及其表观基因组，转录 和表型（蛋白质）特征，以及（2） 提供测试目前批准的非靶向MS新治疗方法的可能性 治疗。由此产生的数据将导致更好地理解组织组织， 功能和基因调控网络。