Defining the contribution of astrocytes to genetic MS susceptibility

定义星形胶质细胞对遗传性多发性硬化症易感性的贡献

• 批准号: 9810339
• 负责人: David Pitt
• 金额: $ 41.23万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810339
• 关键词: Activated Lymphocyte; Affect; Alzheimer' s Disease; Astrocytes; Autopsy; CRISPR/Cas technology; Cell Nucleus; Cell physiology; Cells; Chromatin; Chronic; Complex; Cytometry; Detection; Enhancers; Environment; Flow Cytometry; Freezing; Fumarates; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genetic study; Genotype; Histologic; Human; Image; Immune; Incentives; Individual; Infiltration; Inflammatory; Inflammatory Response; Introns; Knowledge; Lead; Lesion; Link; Lymphocyte; Maps; Mediating; Microglia; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Neuraxis; Neuroglia; Nuclear; Nucleic Acid Regulatory Sequences; Pathology; Pathway interactions; Peripheral; Phenotype; Predisposition; Proteins; Regulator Genes; Resources; Risk; Role; Signal Transduction; TNFRSF1A gene; Testing; Therapeutic Intervention; Tissue Banks; Tissues; Variant; base; brain cell; brain tissue; causal variant; cell type; defined contribution; epigenomics; fluorescence imaging; frontier; genetic variant; genome editing; genome wide association study; genome-wide; individualized medicine; induced pluripotent stem cell; inflammatory marker; inflammatory milieu; macrophage; multiple sclerosis patient; multiple sclerosis treatment; neurotoxicity; new technology; new therapeutic target; recruit; response; risk variant; transcriptome; white matter

Scientific abstract Genome-wide association studies have provided >230 genetic variants associated with susceptibility to multiple sclerosis (MS). The theme emerging from these studies is that MS risk variants perturb gene regulation in activated lymphocytes, supporting the view that MS is mediated through dysregulation of lymphocytes. Absent from this picture is a role for glial cells, despite substantial evidence that these cells are critical players in MS lesion formation. In this proposal, we are challenging the lymphocyte-centric view of genetic MS susceptibility. We hypothesize that genetic variants mediate MS risk in part by dysregulating astrocyte function. Since NF-κB signaling is a central pathway in MS pathology, we will determine the impact of two common NF-κB relevant risk variants, rs1800693G (intronic to TNFRSF1A) and rs7665090G (proximal to NFKB1), on inflammatory response in astrocytes. This will be examined in human astrocyte cultures, derived from genome-edited induced pluripotent stem cells (aim 1), and in reactive astrocytes within active MS lesions (aim 2) with the risk and protective genotypes. In addition, we will quantify variant-driven changes in the lesion environment such as lymphocyte infiltration, lesion size, cellular phenotypes and phenotype interactions. In aim 3, we will systematically identify the MS risk variants that are active in astrocytes and the genes that they perturb. For this, we will generate chromatin accessibility profiles of astrocytes isolated from MS lesions that we will intersect with MS risk variants. The resulting list of variants and variant-dependent genes will provide a roadmap of astroglial pathways that are dysregulated by MS risk variants and thereby are likely to contribute to astrocyte-mediated MS susceptibility. Our results will help to define the role of astrocytes in genetically mediated MS risk. This will provide a more complete picture of how genetic variants confer susceptibility to MS. Moreover, the epigenomic profiles of astrocytes will be an important resource for research in astrocytes and can be used to investigate genetic dysregulation of astrocytes in other complex genetic disease such as Alzheimer’s disease.

科学摘要 全基因组关联研究提供了230个与多发性硬化症易感性相关的遗传变异 硬化症(MS)。从这些研究中得出的主题是多发性硬化症风险变异扰乱了 激活淋巴细胞，支持MS是通过淋巴细胞调节失调来调节的观点。缺席 从这张图中可以看出胶质细胞的作用，尽管有大量证据表明这些细胞在多发性硬化症中起着关键作用。 病变形成。在这个提案中，我们挑战了遗传多发性硬化症易感性的以淋巴细胞为中心的观点。 我们假设遗传变异部分通过星形胶质细胞功能失调来调节多发性硬化症风险。由于核因子-κB 信号转导是多发性硬化病理中的一个中心途径，我们将确定两种常见的NF-κB相关风险的影响 变异体rs1800693G(TNFRSF1A内含子)和rs7665090G(NFKB1近端)对炎症反应的影响 在星形胶质细胞中。这将在人类星形胶质细胞培养中进行检验，这种培养来自基因组编辑的诱导多能性。 干细胞(目标1)和活动期MS病变内反应性星形胶质细胞(目标2)的风险和保护 基因分型。此外，我们将量化病变环境中变异驱动的变化，如淋巴细胞 浸润性、病变大小、细胞表型和表型相互作用。在目标3中，我们将系统地确定 多发性硬化症的风险是星形胶质细胞中活跃的变异体及其干扰的基因。为此，我们将生成 从MS病变中分离的星形胶质细胞染色质可及性谱，我们将与MS风险变异体交叉。 由此产生的变异体和变异体依赖基因的列表将提供星形胶质细胞通路的路线图 多发性硬化症风险变异体的调节失调，从而可能导致星形胶质细胞介导的多发性硬化症易感性。 我们的结果将有助于确定星形胶质细胞在遗传介导的多发性硬化症风险中的作用。这将提供更多 遗传变异如何赋予MS易感性的完整图景此外， 星形胶质细胞将成为研究星形胶质细胞的重要资源，并可用于研究遗传学 在阿尔茨海默病等其他复杂遗传病中，星形胶质细胞的调节失调。