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)转录调控网络和相关信号通路的图谱，亨廷顿病(HD)是一种致命的常染色体显性神经退行性疾病。HD是由亨廷顿蛋白中的CAG扩张导致多谷氨酰胺延伸引起的，其特征是运动、认知和行为功能方面的问题。尽管这种疾病的遗传基础是明确的，但亨廷顿蛋白导致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，即许多先前通过蛋白质组和遗传筛选与HD关联的基因通过信号通路与HD研究中报告的许多转录变化相关联。识别这些途径将为疾病背后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相结合的方法来识别这种信号通路的技术。在特定的目标1中，我们将绘制出转录调节蛋白招募的变化，因为这些蛋白位于信号和表达变化之间的界面上。在特定的目标2中，我们将通过计算确定这些调控因子“上游”的信号变化，这些信号变化将转录变化与基因和蛋白质组数据联系起来。如果成功，这一方法将促进人们对HD病因的认识，并为研究许多人类疾病提供一种强有力的新方法。 公共卫生相关性：我们提出了一种系统生物学方法来理解亨廷顿病发生的分子变化。该项目使用高通量实验和计算建模来揭示疾病中改变的途径，这些途径可能导致新的治疗方法。

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. PUBLIC HEALTH RELEVANCE: We propose a systems biology approach to understanding the molecular changes that occur in Huntington's disease. This project uses high-throughput experiments and computational modeling to reveal pathways that are altered in the disease and that may lead to new therapeutic approaches.