Systems Biology of Insulin Resistance

描述（由申请人提供）：人类肥胖是一个严重的全球性健康问题。肥胖的一个后果是胰岛素抵抗、高血糖和代谢综合征的发展，这些都会导致细胞功能障碍和2型糖尿病。因此，我们了解肥胖发展的生理学和病理生理学是很重要的，因为这些知识代表了设计潜在治疗干预的基础。理解饮食引起的肥胖的一个重大挑战是介导这种反应的信号转导途径的复杂性。事实上，这些信号通路在一个相互作用的网络中起作用。在这里，我们建议采用系统生物学方法，通过将生理分析与信号转导网络和基因组反应的定量分析相结合，来理解对高脂肪饮食的反应。这种分析需要几个具有互补专业知识的实验室的协调合作努力，以及可靠的数据分析和计算建模。我们将集中分析肝脏。本研究计划的总体目标是了解肝脏对饮食引起的肥胖反应的机制。实现这一建议的目标将增加对肥胖分子反应的理解。我们预计，这项研究计划的成功完成将导致信号网络节点的识别，这可能代表了设计治疗代谢综合征和II型糖尿病的新治疗策略的基础。本建议的具体目标是：1。检查肝脏对高脂肪饮食的反应。2. 使用计算建模集成数据分析。3. 通过计算建模得到的测试预测。

DESCRIPTION (provided by applicant): Human obesity represents a serious world-wide health problem. One consequence of obesity is the development of insulin resistance, hyperglycemia, and metabolic syndrome that can lead to cell dysfunction and type 2 diabetes. It is therefore important that we gain an understanding of the physiology and pathophysiology of the development of obesity because this knowledge represents a basis for the design of potential therapeutic interventions. A significant challenge to understanding diet-induced obesity is the complexity of the signal transduction pathways that mediate the response. Indeed, these signaling pathways function within an interacting network. Here we propose to employ a systems biology approach to understanding the response to feeding a high fat diet by combining physiological analysis together with quantitative analysis of the signal transduction networks and the genomic response. This analysis requires the coordinated collaborative efforts of several laboratories with complementary expertise together with robust data analysis and computational modeling. We will focus our analysis on the liver. The overall goal of this research program is to understand the mechanism of the hepatic response to diet-induced obesity. Achievement of the goals of this proposal will increase understanding of the molecular response to obesity. We anticipate that the successful completion of this research program will lead to the identification of nodes in the signaling network that may represent a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type II diabetes. The Specific Aims of this proposal are to: 1. Examine the hepatic response to feeding a high fat diet. 2. Integrate data analysis using computational modeling. 3. Test predictions obtained from computational modeling.