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

基本信息

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
项目类别：
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

项目摘要

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氏症疾病，都表现出不同的临床表现，这些不同的临床表现的基础是。尽管每种疾病中特定神经元细胞类型对死亡或功能障碍的脆弱性增强，但我的工作使用创新方法来解决这些问题。脆弱性加剧这一长期存在的问题，在该领域仍然是一个悬而未决的问题几十年来，我主要参与开发一种广泛使用的细胞类型特异性分析方法，称为“ 我的实验室最近进行了核糖体亲和纯化 (TRAP) 分析，以进行细胞类型特异性 RNA 分析。开发了一种新的中枢神经系统基因体内筛查平台，这是一种强大的大脑研究新方法它可以系统地测试基因组中每个基因对疾病的因果效应（与相关性）表型，而不是测试每只动物的单个基因的更标准方法。单细胞测序方法，我们还进行了亨廷顿舞蹈症最大规模的单细胞研究迄今为止进行的疾病患者组织的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，也与神经元先天免疫激活可能是亨廷顿舞蹈症细胞类型特异性脆弱性的关键驱动因素我的长期研究目标是从亨廷顿舞蹈症作为一种疾病模型开始，阐明其发病机制。神经退行性疾病增强脆弱性的基础，不仅作为发现有价值的窗口深入了解与疾病相关的神经元细胞类型的细胞生物学，同时还确定新的治疗方法目标。