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。肥胖症的一个后果是胰岛素抵抗、高血糖和代谢综合征的发展，其可导致细胞功能障碍和2型糖尿病。因此，重要的是，我们获得的生理学和病理生理学的发展肥胖的理解，因为这方面的知识代表了潜在的治疗干预措施的设计基础。 理解饮食诱导的肥胖的一个重大挑战是介导该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发挥作用。在这里，我们建议采用系统生物学的方法来了解喂养高脂肪饮食的反应，结合生理分析与定量分析的信号转导网络和基因组反应。这种分析需要几个实验室的协调合作，这些实验室具有互补的专业知识，以及强大的数据分析和计算建模。 我们将重点分析肝脏。该研究计划的总体目标是了解肝脏对饮食诱导的肥胖反应的机制。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识别信号网络中的节点，这可能是设计治疗代谢综合征和II型糖尿病的新治疗策略的基础。本提案的具体目标是：1.检查肝脏对高脂饮食的反应。2.使用计算建模集成数据分析。3.从计算模型中获得的测试预测。 公共卫生相关性：代谢综合征和II型糖尿病是严重的疾病，对许多美国人的健康有着深远的影响;我们必须为这些疾病开发新的治疗方案。 本研究计划的目的是对饮食诱导的肥胖症的肝脏反应进行系统生物学分析。我们预计这些信息将为设计治疗代谢综合征和II型糖尿病的新型治疗策略提供基础。

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. PUBLIC HEALTH RELEVANCE: Metabolic syndrome and type II diabetes are serious diseases that have a profound impact on the health of many Americans; it is essential that we develop new treatment options for these diseases. The purpose of this research proposal is to perform a systems biology analysis of the hepatic response to diet-induced obesity. We anticipate that this information will provide a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type II diabetes.