A Systems Biology Approach to Reveal Huntington's Disease Mechanisms

描述（由申请人提供）：我们提出了一种系统生物学方法来绘制亨廷顿病（HD）（一种致命的常染色体显性神经退行性疾病）中改变的转录调控网络和相关信号通路。HD是由CAG扩增导致亨廷顿蛋白中的多聚谷氨酰胺延伸引起的，其特征在于运动、认知和行为功能方面的问题。虽然这种疾病的遗传基础是清楚的，但亨廷顿蛋白引起所观察到的症状的机制仍然是个谜。我们的方法是基于这样的假设，即以前通过蛋白质组学和遗传筛选与HD相关的许多基因通过信号通路与HD研究中报道的许多转录变化相关联。识别这些途径将为疾病基础的分子变化提供关键的新见解，并可能导致新的治疗策略。我们最近开发了一种通过计算和实验方法相结合来识别这种信号通路的技术。在具体目标1中，我们将绘制转录调节蛋白的募集变化，因为这些蛋白质位于信号传导和表达变化之间的界面。在具体目标2中，我们将通过计算确定这些调节因子“上游”的信号变化，这些调节因子将转录变化与遗传和蛋白质组数据联系起来。如果成功，这种方法将推进HD病因学的知识，并为研究许多人类疾病提供一种强大的新方法。

DESCRIPTION (provided by applicant): We propose a Systems Biology approach to map transcriptional regulatory networks and related signaling pathways that are altered in Huntington's disease (HD), a fatal autosomal dominant neurodegenerative disorder. HD is caused by a CAG expansion leading to a polyglutamine extension in the huntingtin protein and is characterized by problems with movement, cognition and behavioral function. Although the genetic basis for the disease is clear, the mechanism by which huntingtin causes the observed symptoms remains enigmatic. Our approach is based on the hypothesis that many of the genes previously linked to HD through proteomic and genetic screens are connected through signaling pathways to many of the transcriptional changes that have been reported in HD studies. Identifying these pathways would provide critical new insights into the molecular changes that underlie the disease, and could lead to novel therapeutic strategies. We have recently developed a technique for identifying such signaling pathways through a combination of computational and experimental methods. In Specific Aim 1 we will map out changes in recruitment of transcriptional regulatory proteins because these proteins lie at the interface between the signaling and expression changes. In Specific Aim 2 we will computationally identify signaling changes "upstream" of these regulators that link the transcriptional changes to the genetic and proteomic data. If successful, this approach will advance knowledge of the etiology of HD and provide a powerful new method for studying many human diseases.