Study on Neurodegeneration Using TDP-43 Transgenic Rats

TDP-43转基因大鼠神经退行性疾病研究

• 批准号: 8191524
• 负责人: hongxia zhou
• 金额: $ 32.46万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191524
• 关键词: Affect; Amyotrophic Lateral Sclerosis; Animal Model; Apoptosis; Apoptotic; Astrocytes; Astrocytosis; Biological Assay; Candidate Disease Gene; Cells; Cessation of life; Complex; Coupled; Dendrites; Development; Disease; Disease Progression; Foundations; Gap Junctions; Genes; Glutamates; Life; Mediating; Mediator of activation protein; Microarray Analysis; Modeling; Motor Neurons; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Paralysed; Pathogenesis; Primary Cell Cultures; Proteins; Quality of life; Rattus; Reaction; Research; Rodent; Signal Transduction; Spinal Cord; Synapses; Toxic effect; Transgenic Organisms; Ubiquitin; base; effective therapy; improved; in vitro Model; in vivo Model; motor neuron degeneration; mutant; neurotoxicity; novel; overexpression; paracrine; prevent; progressive neurodegeneration; protein TDP-43; receptor; response; therapy development; uptake

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) results from progressive degeneration of motor neurons. ALS inexorably progresses to paralysis and to death within an average of 5 years. Of the few treatments, none substantially prolongs life or improves the quality of life. A major hurdle to developing effective therapy for ALS is a limited understanding of the disease mechanisms. A recent advance in ALS research comes with the discovery of TDP- 43 proteinopathy and TDP mutation. When overexpressed in transgenic rodents, mutant TDP-43 causes progressive neurodegeneration accompanied by severe glial reaction. To dissect the mechanisms underlying neurodegeneration caused by TDP mutation, we have developed transgenic rats reversibly expressing mutant TDP-43 in neurons or in astrocytes. By microarray analysis, we also have identified candidate genes responsive to glial reaction in mutant TDP-43 transgenic rats. Using TDP-43 transgenic rats (in vivo model) and primary cell cultures (in vitro model) as complementary models, we will resolve the following critical questions regarding TDP-43 pathogenesis: 1) how glial reaction correlates with the neurodegeneration caused by TDP mutation; 2) whether presence of mutant TDP-43 in astrocytes accelerates glial activation; 3) what molecules mediate the propagation of glial reaction in response to TDP mutation; 4) how astrocytes expressing mutant TDP-43 produce neurotoxicity; 5) how expression of mutant TDP-43 in astrocytes affects onset and progression of ALS in transgenic rats; and 6) whether continuous presence of mutant TDP-43 is required for disease progression. Proposed studies will not only develop desirable animal models for ALS research, but also would establish a foundation for developing ALS therapies targeting astrocytes or mutant TDP-43. PUBLIC HEALTH RELEVANCE: Using transgenic rats and primary cells as complementary models, this proposal will dissect the mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis and will provide a foundation for developing ALS therapies.

描述（由申请人提供）：肌萎缩性侧性硬化症（ALS）是由于运动神经元的进行性变性而导致的。 ALS无可避免地发展为瘫痪，平均在5年内死亡。在少数治疗方法中，没有一个实质性地延长寿命或改善生活质量。对ALS开发有效疗法的主要障碍是对疾病机制的有限理解。 ALS研究的最新进展是发现TDP-43蛋白质病和TDP突变。当过表达转基因啮齿动物时，突变体TDP-43会导致进行性神经退行性伴随着严重的神经胶质反应。为了剖析TDP突变引起的神经变性的基本机制，我们开发了转基因大鼠，可逆地表达神经元或星形胶质细胞中的突变体TDP-43。通过微阵列分析，我们还确定了对突变体TDP-43转基因大鼠中神经胶质反应有反应的候选基因。将TDP-43转基因大鼠（体内模型）和原代细胞培养物（体外模型）作为互补模型，我们将解决有关TDP-43发病机理的以下关键问题：1）神经胶质反应如何与由TDP突变引起的神经变性纠正； 2）星形胶质细胞中突变的TDP-43是否会加速神经胶质激活； 3）什么分子介导了响应TDP突变的胶质反应的传播； 4）表达突变体TDP-43的星形胶质细胞如何产生神经毒性； 5）星形胶质细胞中突变体TDP-43的表达如何影响转基因大鼠ALS的发作和进展； 6）疾病进展是否需要连续存在突变的TDP-43。拟议的研究不仅将开发出理想的动物模型用于ALS研究，而且还将为开发针对星形胶质细胞或突变体TDP-43的ALS疗法建立基础。 公共卫生相关性：使用转基因大鼠和原代细胞作为互补模型，该提案将在肌萎缩性侧索硬化症中剖析运动神经元变性的机制，并将为开发ALS疗法提供基础。