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

描述(申请人提供)：亨廷顿病(HD)是一种遗传性神经退行性疾病，影响美国超过10万人的生活，由4p16.3 HD基因中不稳定的CAG重复引起，该基因编码亨廷顿蛋白中的可变聚谷氨酰胺链。这项资助的目标仍然是利用小鼠HD基因同源基因(HDH)中的靶向突变来描绘这一有趣的致病机制及其在纹状体中的最早后果，为确定修改疾病过程中最早步骤的因素提供分析。我们的研究包括三个新目标。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多梳抑制复合体(PRC2/3)的功能和组蛋白3甲基转移酶活性有关，并对其进行调节。目的1验证这一假说，并确定亨廷顿蛋白中多谷氨酰胺束的延长是否可能与亨廷顿蛋白在HD触发机制中的活性有关。目的2将确定纹状体对HD CAG重复的即刻早期基因反应的转录调控因子，包括Nrf1/E2F衰老靶基因。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将测试这样一种假设，即突变的Huntingtin仅在中等大小的纹状体神经元中有条件地表达将足以引发早期疾病级联，表明修改疾病过程的过程是这些细胞固有的。这些研究将提供有价值的信息和分析方法，用于识别可能干扰HD触发机制及其对纹状体神经元的早期影响的基因和化合物，纹状体神经元是HD患者中最薄弱的一环。

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.