Regulation of Lipid Homeostasis in C. elegans

描述（由申请人提供）：过去二十年来，肥胖、动脉粥样硬化、II型糖尿病和高血压的发病率显著增加，这些都与代谢综合征有关。导致代谢综合征的潜在分子缺陷尚不明确。复杂的调节机制和不同器官在指导代谢和脂质/能量稳态中的相互作用将需要在整个生物体的背景下进行研究。我们建议研究秀丽隐杆线虫脂质稳态调节的保守机制。许多哺乳动物调节能量和脂质稳态的信号通路和调控回路，如胰岛素信号通路和转录因子SREBP（一种参与胆固醇和脂肪酸稳态的重要调控基因），在秀丽隐杆线虫中是保守的。

DESCRIPTION (provided by applicant): The last two decades have witnessed a striking increase in obesity, atherosclerosis, type II diabetes, and hypertension, all associated with metabolic syndrome. The underlying molecular defects contributing to metabolic syndrome are poorly defined. Complex regulatory mechanisms and interplay of different organs in guiding metabolism and lipid/energy homeostasis will necessitate studies in the context of whole organisms. We are proposing to investigate conserved mechanisms of regulation of lipid homeostasis in the nematode Caenorhabditis elegans. Many mammalian signaling pathways and regulatory circuitries modulating energy and lipid homeostasis, such as the insulin signaling pathway and the transcription factor SREBP, an important regulator of genes involved in cholesterol and fatty acid homeostasis, are conserved in C. elegans. C. elegans also has several advantages over more complex model systems, including short generation time and the ease of whole-organism RNAi screens. The Specific Aims are: 1. To determine the role of the SREBP homolog SBP-1 and cognate co-activators in regulation of lipid homeostasis in C. elegans. 2. To evaluate the role of the insulin/IGF-1 signaling pathway in regulating SBP-1 and C. elegans lipid homeostasis. 3. To identify novel regulators of fatty acid desaturation and lipid homeostasis in C. elegans. We propose to perform RNAi-based screens to identify novel conserved regulators of lipid homeostasis. The long-term objectives are to identify and characterize key conserved regulators of lipid biology that could contribute to dysregulation of energy/lipid homeostasis and metabolic syndrome in humans.