The Role of Astrocytes in Huntington's Disease

描述（由申请人提供）：亨廷顿病（HD）是一种成人发病的常染色体显性神经退行性疾病，临床特征为认知、精神和运动缺陷，可发展为严重残疾和死亡。到目前为止，还没有有效的治疗HD。突变的亨廷顿蛋白（mhtt）在神经元和非神经元细胞中广泛表达，但神经变性具有高度选择性。了解mhtt产生的毒性和这种选择性神经变性的基础，对于设计有效的治疗方法可能是至关重要的。 该提案的目标是了解表达mhtt的星形胶质细胞对HD中神经变性的贡献。星形胶质细胞对神经系统的正常功能和发育至关重要，并在控制突触活动方面具有新的作用。来自细胞培养研究的数据显示星形胶质细胞可能有助于HD发病机制。然而，尚未进行体内研究来系统地解决这个问题。因此，我将通过使用条件性mhtt表达小鼠遗传模型来研究星形胶质细胞在体内疾病发病机制中的作用。 使用这些模型和从它们获得的星形胶质细胞，我将测试三个假设：1）星形胶质细胞中mhtt的存在是（1）HD表型的发展所必需和充分的; 2）星形胶质细胞中mhtt的存在导致钙稳态受损和星形胶质细胞释放谷氨酸;和3）星形胶质细胞中mhtt的存在导致突触神经传递异常。这些研究将有助于确定星形胶质细胞内的mhtt在HD发病机制中的作用，并可能导致新的治疗方法治疗HD。 本申请中的研究计划旨在使申请人获得额外的技术技能和工具，用于研究亨廷顿病的发病机制，包括细胞生物学和电生理学。这些新的能力，再加上以前在生成神经退行性变的小鼠遗传模型方面的培训，将使她成为一名多学科科学家，拥有实现她在一家主要研究机构获得终身教职的长期职业目标所需的全面技能。除了在培训期间获得的技术技能外，申请人还将通过参加UAB和外部科学会议的研讨会和期刊俱乐部来进一步了解神经退行性疾病。她还将利用教师发展研讨会和课程，帮助教授所需的技能，并提供作为独立研究科学家的成功职业所需的知识，包括科学和赠款写作技能。该申请的职业发展部分和研究计划将为候选人提供一个坚实的基础，以建立一个专注于研究神经退行性疾病的独立实验室。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is an adult-onset autosomal dominant neurodegenerative disorder characterized clinically by cognitive, psychiatric and motor deficits which progress to severe disability and death. To date there are no affective treatments for HD. The mutated huntingtin (mhtt) protein is widely expressed in neuronal and non-neuronal cells, yet neurodegeneration is highly selective. Understanding the toxicity produced by mhtt and the basis for this selective neurodegeneration are likely to be critical in the design of effective therapies for the disease. The goal of this proposal is to understand the contribution of mhtt expressing astrocytes to neurodegeneration in HD. Astrocytes are critical to the proper function and development of the nervous system and have a newly appreciated role in controlling synaptic activity. Data from cell culture studies show that astrocytes may contribute to HD pathogenesis. However, no in vivo studies have been performed to systematically address this question. Therefore, I will study the contribution of astrocytes to disease pathogenesis in vivo by using conditional mhtt expressing mouse genetic models. Using these models and astrocytes obtained from them I will test three hypotheses: 1) The presence of the mhtt in astrocytes is (1) necessary and sufficient for the development of an HD phenotype; 2) the presence of mhtt in astrocytes causes impaired calcium homeostasis and glutamate release from astrocytes; and 3) The presence of mhtt in astrocytes leads to abnormalities in synaptic neurotransmission. Together these studies will help to define the role of mhtt within astrocytes in HD pathogenesis, and may lead to novel therapeutic approaches for treatment of HD. The research plan in this application is designed to allow the applicant to gain additional technical skills and tools for use in studying Huntington's disease pathogenesis, including cell biology and electrophysiology. These new capabilities, together with previous training in generating mouse genetic models of neurodegeneration, will make her a multidisciplinary scientist with the well-rounded set of skills necessary for attaining her long-term career goal of acquiring a tenure track faculty appointment at a major research institution. In addition to the technical skills obtained during this training period, the applicant will further her understanding of neurodegenerative diseases by attending seminars and journal clubs at UAB and outside scientific meetings. She will also take advantage of faculty development seminars and programs that help to teach the required skills and provide the knowledge necessary for a successful career as an independent research scientist including scientific and grant writing skills. Together, the career development component and research plan of this application will provide the candidate with a firm foundation on which to develop an independent laboratory focused on studying neurodegenerative diseases.