Regulation of Lipid Homeostasis in C. elegans

描述(由申请人提供)：在过去的二十年里，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，所有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还没有明确的定义。复杂的调节机制和不同器官在指导新陈代谢和脂质/能量平衡方面的相互作用将需要在整个生物体的背景下进行研究。我们建议研究线虫体内脂类平衡调节的保守机制。许多哺乳动物调节能量和脂肪稳态的信号通路和调节电路，如胰岛素信号通路和转录因子SREBP，是参与胆固醇和脂肪酸稳态基因的重要调节因子，在线虫中是保守的。 与更复杂的模型系统相比，线虫还有几个优势，包括生成时间短，以及易于进行全生物RNAi筛选。具体目标是： 1.确定SREBP同系物SBP-1和同源共激活子在线虫体内调节脂质稳态中的作用。 2.探讨胰岛素/IGF-1信号通路在调节SBP-1和线虫脂质稳态中的作用。 3.鉴定线虫脂肪酸去饱和和脂平衡的新调节因子。我们建议进行基于RNAi的筛选，以确定新的保守的脂质稳态调节因子。 长期目标是确定和表征可能导致人类能量/脂平衡失调和代谢综合征的脂类生物学的关键保守调节因子。

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.