Delineating the Huntington's disease mechanism by manipulating the mouse HD

描述（由申请人提供）：亨廷顿氏病（HD）是一种遗传性神经退行性疾病，在美国影响超过10万人的生活，是由编码亨廷顿蛋白可变聚谷氨酰胺通道的4p16.3 HD基因中不稳定的CAG重复引起的。这项资助的目标是利用小鼠HD基因同源物（Hdh）的靶向突变来描述这种有趣的疾病启动机制及其在纹状体中的早期后果，为识别改变疾病过程中最早步骤的因素提供检测方法。我们的研究包括三个新的目标。在探索亨廷顿蛋白在hd触发机制中的作用时，我们发现亨廷顿蛋白可能与Eed polycomb suppressicomplex （PRC2/3）的功能和组蛋白3甲基转移酶活性相关并进行调控。目的1将检验这一假设，并确定延长多聚谷氨酰胺束对亨廷顿蛋白的影响是否与亨廷顿蛋白活性在HD触发机制中的作用有关。Aim 2将确定纹状体对HD CAG重复序列的即时早期基因反应的转录调节因子，包括Nrf1/E2F衰老靶基因，导致大多数HD病例。为了确定使纹状体神经元如此容易受到hd触发器影响的因素，Aim 3将测试假设，即仅在中等大小的棘状纹状体神经元中有条件表达突变的亨廷顿蛋白足以引发早期疾病级联，这表明改变疾病过程的过程是这些细胞固有的。这些研究将为识别可能干扰HD触发机制及其在纹状体神经元中的早期影响的基因和化合物提供有价值的信息和分析，纹状体神经元是HD患者最薄弱的环节。

DESCRIPTION (provided by applicant): Huntington's disease (HD), an inherited neurodegenerative disorder that affects the lives of more than 100,000 people in the US, is caused by an unstable CAG repeat in the 4p16.3 HD gene that encodes a variable polyglutamine tract in huntingtin. This grant continues to have the goal of using targeted mutations in the mouse's HD gene homolog (Hdh) to delineate this intriguing disease-initiating mechanism and its earliest consequences in striatum, to provide assays for identifying factors that modify the earliest steps in the disease process. Our studies comprise three new Aims. In exploring huntingtin function in the HD-trigger mechanism we have found that huntingtin may associate with and regulate the function and histone 3 methyltransferase activity of Eed polycomb repressive complex (PRC2/3). Aim 1 will test this hypothesis and determine whether the effects of lengthening the polyglutamine tract in huntingtin may implicate huntingtin activity in the HD trigger mechanism. Aim 2 will identify the transcriptional regulators of the immediate early gene response in striatum to the HD CAG repeat that causes the majority of HD cases, including Nrf1/E2F senescence target genes. To identify factors that make striatal neurons so vulnerable to the effects of the HD-trigger, Aim 3 will test the hypothesis that conditional expression of mutant huntingtin only in medium sized spiny striatal neurons will be sufficient to elicit the early disease cascade, indicating that the processes that modify the disease process are intrinsic to these cells. These studies will yield valuable information and assays for identifying genes and compounds that may interfere with the HD-trigger mechanism and its early effects in the striatal neurons that are the weakest link in HD patients.