Transcriptome in Huntington's disease and Huntington's disease-like 2

描述（由申请人提供）：亨廷顿病（HD）和亨廷顿病样2 （HDL2）是非常相似的常染色体显性成人发病神经退行性疾病，在临床和病理上几乎无法区分。每种疾病最终都是致命的，没有有效的治疗方法来阻止或减缓这种无情的进展。大约有3万美国人患有HD，患病风险更高；HDL2是罕见的。HD和HDL2发病机制的完整解释仍然难以捉摸。一种聚焦于HD疾病机制和治疗靶点的新策略是确定HD和HDL2的致病途径汇合的点。实施这一策略的一个特别有效的方法是比较这两种疾病的转录组。根据我们的初步证据，我们假设在HD和HDL2中都存在异常水平的基因表达和异常基因剪接，并且这些异常的集合在两种疾病中会重叠。在这里，我们建议利用HD和HDL2的显著相似性，通过对HD和HDL2的小鼠模型和人类患者样本的平行转录组特征来识别趋同的致病途径。我们提出两个具体目标。在目标1中，我们将使用最先进的外显子连接阵列，RNA测序（RNA- seq）和分析方法来检查和比较从人类HD和HDL2死后大脑和HD和HDL2小鼠模型以及对照中提取的RNA。在目标2中，我们将使用高通量自动PCR分析和新的RNA样本实验验证表达和剪接异常，比较小鼠和人类数据，并使用生物信息学工具确定HD和HDL2大脑中显示基因表达或剪接异常的基因共享的共同基因集、途径和分子亚网络。我们预计，拟议的研究将创造一个极其宝贵的资源，以前所未有的分辨率提供HD和HDL2转录组的详细特征，从而从根本上提高对疾病病理生理学的理解。

DESCRIPTION (provided by applicant): Huntington's disease (HD) and Huntington's disease-like 2 (HDL2) are remarkably similar autosomal dominant adult onset neurodegenerative disorders, nearly indistinguishable clinically and pathologically. Each disease is ultimately fatal with no effective treatment to stop or slow the relentless progression. HD affects about 30,000 Americans, with a much higher number at risk; HDL2 is rare. The complete explanation for HD and HDL2 pathogenesis remains elusive. A novel strategy for focusing the search for disease mechanisms and therapeutic targets of HD is to determine those points at which the pathogenic pathways of HD and HDL2 converge. A particularly powerful method for implementing this strategy is to compare the transcriptomes of the two diseases. Based on our preliminary evidence, we hypothesize that both abnormal levels of gene expression and abnormal gene splicing will be present in HD and HDL2 and that the sets of these abnormalities will overlap in the two diseases. Here we propose to take advantage of the remarkable similarities of HD and HDL2 to identify convergent pathogenic pathways, via parallel transcriptome characterization of mouse models and human patient samples of HD and HDL2. We propose two specific aims. In aim 1, we will use state of the art exon junction array, RNA sequencing (RNA-Seq), and analytic methods to examine and compare RNA extracted from human HD and HDL2 postmortem brains and mouse models of HD and HDL2 as well as controls. In aim 2, we will experimentally validate expression and splicing abnormalities using high-throughput automated PCR assays and new RNA samples, compare mouse and human data, and use bioinformatics tools to determine common gene sets, pathways, and molecular subnetworks shared by genes showing gene expression or splicing abnormalities in HD and HDL2 brains. We anticipate that the proposed studies will create an extremely valuable resource that will provide a detailed characterization of the HD and HDL2 transcriptomes at an unprecedented resolution and hence fundamentally improve understanding of disease pathophysiology. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) and Huntington's disease-like 2 (HDL2) are remarkably similar autosomal dominant adult onset neurodegenerative disorders, nearly indistinguishable clinically and pathologically. This project will conduct a comprehensive examination and comparison of HD and HDL2 transcriptomes to identify defects in gene expression and splicing in diseased brains. These studies will lead to a better understanding of HD and HDL2 pathophysiology, and may reveal novel molecular targets and pathways for therapeutic development.