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: 10614595
• 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/10614595
• 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.

摘要 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氏症 所有的疾病都有不同的临床表现。这些独特的临床表现的基础是 在每种疾病中，特定神经细胞类型对死亡或功能障碍的易感性增加，尽管 疾病相关基因的广泛表达。我的工作使用创新的方法来解决这些问题 关于增强脆弱性的长期问题，这些问题在实地仍然是悬而未决的问题 几十年。我主要参与开发了一种广泛使用的特定细胞类型的分析方法，称为 翻译核糖体亲和纯化(TRAP)，允许特定细胞类型的RNA图谱。我的实验室最近 为中枢神经系统开发了一个新的遗传体内筛选平台，为脑研究提供了一种强大的新方法，如 它允许系统地测试疾病基因组中每个基因的因果关系(与相关性)。 表型，而不是更标准的方法，测试每只动物的单一基因。此外，使用 单细胞测序方法，我们还进行了亨廷顿氏病最大的单细胞研究 到目前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 亨廷顿病和亨廷顿病模型组织中的失调，也牵涉到 神经元天然免疫激活可能是亨廷顿病细胞类型特异性易损性的关键驱动因素 疾病。我的长期研究目标是，从亨廷顿氏病作为一种典型障碍开始，阐明 神经退行性疾病脆弱性增强的基础，不仅是发现有价值的 对疾病相关神经细胞类型的细胞生物学的洞察，也识别新的治疗方法 目标。