Molecular Mechanisms Underlying Cell Type-Specific Vulnerability in Huntington’s Disease

亨廷顿病细胞类型特异性脆弱性的分子机制

• 批准号: 10457670
• 负责人: Myriam Heiman
• 金额: $ 54.29万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2030-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10457670
• 关键词: Address; Affinity Chromatography; Alzheimer' s Disease; Animals; Brain; Cells; Cellular biology; Cessation of life; Clinical; Disease; Disease model; Functional disorder; Genes; Genetic; Genetic Transcription; Genome; Goals; Huntington Disease; Methodology; Molecular; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathologic; Pathway interactions; Patients; RNA; Research; Ribosomes; Testing; Tissue Model; Tissues; Translating; Work; age related neurodegeneration; cell type; disease phenotype; immune activation; in vivo; innovation; insight; new therapeutic target; novel strategies; screening; single cell sequencing; therapeutic target; therapeutically effective

Abstract The most common neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, all display distinct clinical presentations. The basis of these distinct clinical presentations is the enhanced vulnerability of specific neuronal cell types to death or dysfunction in each disease, despite widespread expression of disease-associated genes. My work uses innovative approaches to address these long-standing questions of enhanced vulnerability, which have remained open questions in the field for decades. I was centrally involved in developing a widely used cell type-specific profiling methodology known as translating ribosome affinity purification (TRAP) that allows cell type-specific RNA profiling. My lab has recently developed a new genetic in vivo screening platform for the CNS, a powerful new approach for brain studies as it allows for systematically testing the causal effect (versus correlation) of each gene in the genome for disease phenotypes, rather than more standard approaches that test a single gene per animal. Additionally, using single cell sequencing approaches, we have also conducted the largest single cell studies of Huntington’s disease patient tissue conducted to date. These studies have collectively revealed the scope of transcriptional dysregulation in Huntington’s disease and Huntington’s disease model tissue, and also have implicated neuronal innate immune activation as a likely key driver of cell type-specific vulnerability in Huntington’s disease. My long-term research goal, starting with Huntington’s disease as a model disorder, is to elucidate the basis of enhanced vulnerability in neurodegenerative disease, not only as a window for discovering valuable insights into the cell biology of disease-relevant neuronal cell types, but also identifying new therapeutic targets.

抽象的 最常见的神经退行性疾病，包括阿尔茨海默氏症，帕金森氏症和亨廷顿的 疾病，均显示出不同的临床表现。这些独特的临床演示的基础是 在每种疾病中，特定神经元细胞类型的死亡或功能障碍的脆弱性增强了dospite 与疾病相关基因的宽度表达。我的工作使用创新的方法来解决这些问题 长期存在增强脆弱性的问题，这些问题在现场仍然是空旷的问题 几十年。我集中参与开发广泛使用的细胞类型特异性分析方法，称为 翻译核糖体亲和力纯化（TRAP），允许细胞类型特异性RNA分析。我的实验室最近有 开发了一个新的CNS遗传体内筛选平台，这是一种强大的脑研究方法 它允许系统地测试疾病基因组中每个基因的因果效应（与相关性） 表型，而不是每只动物单个基因的更多标准方法。另外，使用 单细胞测序方法，我们还进行了亨廷顿最大的单细胞研究 迄今为止进行的疾病患者组织。这些研究共同揭示了转录的范围 亨廷顿氏病和亨廷顿氏病模型组织的失调，也实施了 神经元的先天免疫激活是亨廷顿的细胞类型特异性脆弱性的主要驱动力 疾病。我的长期研究目标是从亨廷顿氏病作为模型障碍开始的，是为了阐明 神经退行性疾病中脆弱性增强的基础，不仅是发现价值的窗口 洞悉与疾病相关的神经元细胞类型的细胞生物学，但也识别出新的疗法 目标。