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: 10598564
• 负责人: David Pitt
• 金额: $ 32.56万
• 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/10598564
• 关键词: Activated Lymphocyte; Affect; Alzheimer' s Disease; Astrocytes; Autopsy; CRISPR/Cas technology; Cell Nucleus; Cell physiology; Cells; Central Nervous System; Chromatin; Chronic; Complex; Cytometry; Detection; Enhancers; Environment; Flow Cytometry; Freezing; Fumarates; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic study; Genotype; Histologic; Human; Image; Immune; Incentives; Individual; Inflammatory; Inflammatory Response; Introns; Knowledge; Lesion; Link; Lymphocyte; Lymphocytic Infiltrate; Macrophage; Maps; Mediating; Microglia; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; 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; 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; multiple sclerosis patient; multiple sclerosis treatment; neurotoxicity; new technology; new therapeutic target; protective allele; 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种与多种易感性相关的遗传变异 硬化症（MS）。这些研究中出现的主题是MS风险变异扰动基因调节 活化的淋巴细胞，支持MS通过淋巴细胞失调介导的观点。缺席的 从这张图中，目的地是神经胶质细胞的作用，证据表明这些细胞是MS中的关键参与者 病变形成。在此提案中，我们挑战了以遗传MS敏感性为中心的淋巴细胞观点。 我们假设遗传变体通过失调的星形胶质细胞功能来部分介导MS风险。自NF-κB以来 信号传导是MS病理学中的中心途径，我们将确定两个常见的NF-κB相关风险的影响 变体，RS1800693G（TNFRSF1A内含子）和RS7665090G（NFKB1近端） 在星形胶质细胞中。这将在人类星形胶质细胞培养物中进行检查，该培养物从基因组编辑的诱导多能衍生 干细胞（AIM 1），在活跃的MS病变内的反应性星形胶质细胞中（AIM 2）有风险并保护 基因型。此外，我们将量化病变环境中的变体驱动变化，例如淋巴细胞 在AIM 3中，我们将系统地识别 在星形胶质细胞中活跃的MS风险变体及其扰动的基因。为此，我们将生成 从MS病变中分离出的星形胶质细胞的染色质可及性轮廓，我们将与MS风险变体相交。 由此产生的变体和变体依赖性基因的列表将提供星形胶质途径的路线图 由于MS风险变异的失调，因此可能会导致星形胶质细胞介导的MS易感性。 我们的结果将有助于定义星形胶质细胞在一般介导的MS风险中的作用。这将提供更多 完整的遗传变体会议易感性的完整图片。此外， 星形胶质细胞将是星形胶质细胞研究的重要资源，可用于研究通用 其他复杂遗传疾病（例如阿尔茨海默氏病）中星形胶质细胞的失调。