Modifiers of Polyglutamine Toxicity

聚谷氨酰胺毒性调节剂

• 批准号: 6917180
• 负责人: ANDREW P LIEBERMAN
• 金额: $ 20.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917180
• 关键词: HeLa cells; acetylation; androgen receptor; animal genetic material tag; cell death; chemical aggregate; disease /disorder onset; fibroblasts; gene mutation; genetically modified animals; heat shock proteins; histopathology; homopeptide; laboratory mouse; muscle function; neoplastic cell culture for noncancer research; neural degeneration; neuropathology; neurotoxicology; nucleic acid repetitive sequence; phenotype; posttranslational modifications; protein folding; protein protein interaction; protein structure function; serial analysis of gene expression

DESCRIPTION (provided by applicant): Chronic neurodegenerative diseases are a significant health problem for the elderly, causing profound morbidity and mortality, and generating staggering health care related expenses. Mechanisms that regulate the late onset and severity of phenotype of these disorders are poorly understood. To address this question we have chosen to study Kennedy's disease, a degenerative disorder of motor neurons caused by a CAG/glutamine expansion in the androgen receptor. The laboratory's long-range goal is to understand the mechanisms by which expansions of glutamine tracts cause neuronal dysfunction and death. The objective of this application is to identify pathways that modify toxicity of the mutant androgen receptor, and may therefore impact age of onset and severity of phenotype. Our central hypothesis is that toxicity is modified both by the unfolded protein response (UPR) and by decreased receptor acetylation. The rationale of these studies is that understanding pathways that modify toxicity of the mutant protein will yield insights into the mechanisms of neurodegeneration, thereby suggesting novel therapeutic targets. The central hypothesis will be tested by pursuing the following specific aims: 1) Establish that the UPR is a modifier of polyglutamine toxicity; 2) Determine the extent to which decreased acetylation of the expanded glutamine androgen receptor contributes to misfolding and aggregation; and 3) Determine the extent to which 113 CAG repeats targeted to the mouse androgen receptor gene causes selective dysfunction or degeneration of motor neurons, UPR activation and decreased receptor acetylation in vivo. It is my expectation that receipt of the Beeson Award will enable me to gain critical skills and experience in aging research. At the completion of these studies, we expect to establish that misfolding, aggregation and toxicity of the mutant androgen receptor is modified by the UPR and by pathways that mediate ligand-dependent androgen receptor acetylation. We also expect that our knock-in mouse model will reproduce important aspects of this disorder, including selective motor neuron dysfunction and degeneration. Such outcomes will have general impact by furthering our understanding of disease pathogenesis and by yielding a mouse model that faithfully recapitulates the human disease.

描述（由申请人提供）：慢性神经退行性疾病是老年人的重大健康问题，导致了严重的发病率和死亡率，并产生了惊人的医疗保健相关费用。调节这些疾病表型晚期发作和严重程度的机制知之甚少。为了解决这个问题，我们选择研究肯尼迪氏病，肯尼迪氏病是由雄激素受体中CAG/谷氨酰胺扩张引起的运动神经元的退化性疾病。实验室的远程目标是了解谷氨酰胺区扩张引起神经元功能障碍和死亡的机制。该应用的目的是确定改变突变雄激素受体毒性的途径，因此可能影响表型的发作和严重程度的年龄。我们的中心假设是，毒性是通过展开的蛋白质反应（UPR）和受体乙酰化降低来改变的。这些研究的理由是，了解改变突变蛋白毒性的途径将产生对神经变性机制的见解，从而提出新的治疗靶标。中央假设将通过追求以下特定目的进行检验：1）确定UPR是聚谷氨酰胺毒性的修饰符； 2）确定扩展的谷氨酰胺雄激素受体的乙酰化减少的程度有助于折叠和聚集； 3）确定针对小鼠雄激素受体基因的113个CAG重复的程度会导致运动神经元的选择性功能障碍或变性，UPR激活和体内受体乙酰化降低。我期望获得Beeson Award的收到将使我能够在衰老研究中获得关键的技能和经验。这些研究完成时，我们希望确定突变雄激素受体的错误折叠，聚集和毒性通过UPR和介导依赖配体依赖性雄激素受体乙酰化的途径来改变。我们还期望我们的敲入小鼠模型将重现该疾病的重要方面，包括选择性运动神经元功能障碍和变性。这种结果将通过进一步了解疾病发病机理的理解并产生忠实地概括人类疾病的小鼠模型来产生一般影响。