The Role of Astrocytes in Huntington's Disease

星形胶质细胞在亨廷顿病中的作用

• 批准号: 8456153
• 负责人: Michelle Gray
• 金额: $ 17.48万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456153
• 关键词: Address; Adult; Affective; Appointment; Astrocytes; Bacterial Artificial Chromosomes; Behavioral; Brain; Buffers; Calcium; Cell Culture Techniques; Cells; Cellular biology; Cessation of life; Cognitive; Corpus striatum structure; Data; Development; Diagnosis; Disease; Disease model; Educational process of instructing; Electrophysiology (science); Extracellular Space; Faculty; Foundations; Gene Transfer Techniques; Genes; Genetic Models; Glial Fibrillary Acidic Protein; Glutamate Transporter; Glutamates; Goals; Grant; Homeostasis; Human; Huntington Disease; In Vitro; Institution; Journals; Knowledge; Laboratories; Lead; Length; Mechanical Stimulation; Methods; Mitochondria; Modeling; Mus; Mutate; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neurons; Neurotransmitters; Pathogenesis; Pathway interactions; Patients; Phenotype; Research; Risk; Role; Scientist; Site; Structure; Synapses; Testing; Toxic effect; Training; Transgenes; Transgenic Mice; Writing; base; career; career development; cell type; design; disability; disease phenotype; effective therapy; extracellular; hippocampal pyramidal neuron; human Huntingtin protein; in vivo; meetings; motor deficit; mouse model; multidisciplinary; mutant; nervous system development; neurotransmission; novel; novel therapeutic intervention; polyglutamine; programs; public health relevance; skills; tool; transgene expression; uptake; voltage clamp

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.

描述(申请人提供)：亨廷顿病(HD)是一种成人起病的常染色体显性神经退行性疾病，临床特征是认知、精神和运动障碍，进展为严重残疾和死亡。到目前为止，还没有针对HD的有效治疗方法。突变的亨廷顿蛋白(MHTT)在神经细胞和非神经细胞中广泛表达，但神经退行性变具有高度的选择性。了解mHTT产生的毒性和这种选择性神经变性的基础可能对设计有效的治疗方法至关重要。本研究的目的是了解mHTT表达的星形胶质细胞在HD神经变性中的作用。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发挥着新的作用。细胞培养研究的数据显示，星形胶质细胞可能参与HD的发病。然而，还没有进行体内研究来系统地解决这个问题。因此，我将利用表达条件mHTT的小鼠遗传模型，在体内研究星形胶质细胞在疾病发病机制中的作用。使用这些模型和从中获得的星形胶质细胞，我将检验三个假设：1)星形胶质细胞中mHTT的存在是(1)HD表型形成的必要条件和充分条件；2)星形胶质细胞中mHTT的存在导致星形胶质细胞钙稳态和谷氨酸释放受损；以及3)星形胶质细胞中mHTT的存在导致突触神经传递的异常。总之，这些研究将有助于确定星形胶质细胞中mHTT在HD发病机制中的作用，并可能导致HD治疗的新的治疗方法。本申请中的研究计划旨在使申请者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，加上之前在建立神经退化的老鼠遗传模型方面的培训，将使她成为一名多学科科学家，拥有一套全面的技能，以实现她在一家大型研究机构获得终身教职的长期职业目标。除了在培训期间获得的技术技能外，申请者还将通过参加UAB的研讨会和杂志俱乐部以及外部的科学会议来加深她对神经退行性疾病的理解。她还将利用教师发展研讨会和项目，帮助教授必要的技能，并提供作为一名独立研究科学家成功职业生涯所必需的知识，包括科学和拨款写作技能。总之，这项申请的职业发展部分和研究计划将为应聘者提供坚实的基础，在此基础上建立一个专注于研究神经退行性疾病的独立实验室。