Genetic and Genomic Investigations of Fat Storage and Metabolism in C. elegans

描述（申请人提供）：秀丽隐杆线虫脂肪储存和代谢的遗传和基因组研究。肥胖困扰着数百万世界公民。与肥胖相关的健康问题正在以流行病的速度上升，这对世界卫生保健系统提供充分的保健提出了挑战。这项研究的长期目标是剖析脂肪调节的途径，以更好地理解特定基因促进或促进对肥胖的抵抗的机制。我们在模式生物秀丽隐杆线虫中的工作已经导致了脂质稳态保守调节因子的鉴定。这些研究的核心假设是，脂肪储存的变化是调节途径和下游脂质代谢基因相互作用的结果。该资助旨在鉴定关键转录调控因子NHR-64和DAF-16/FoxO下游的脂肪调控和脂肪调节基因。我们将通过基因表达研究、遗传上位分析、RNA干扰功能研究和脂质分析来探讨脂质调节剂的鉴定、功能作用及其在遗传调控体系中的地位。广泛收集的突变体，加上秀丽隐杆线虫中强大的遗传和基因组资源，将允许对调节脂肪储存的分子进行快速功能评估，并更好地了解它们与其他脂肪调节途径的相互作用。

DESCRIPTION (provided by applicant): Genetic and genomic investigations of fat storage and metabolism in C. elegans. Obesity afflicts millions of world citizens. The health problems associated with obesity are rising at epidemic rates, challenging world health care systems to provide adequate care. The long-term goal of this research is to dissect the pathways of fat regulation to better understand the mechanisms by which specific genes act to either promote or facilitate resistance to obesity. Our work in the model organism Caenorhabditis elegans has led the identification of conserved regulators of lipid homeostasis. The central hypothesis underlying these studies is that changes in fat stores occur as a result of interactions between regulatory pathways and downstream lipid metabolism genes. This grant proposes to identify fat-regulatory and fat-modulating genes downstream of the key transcriptional regulators NHR-64 and DAF-16/FoxO. The identification of lipid regulators, their functional roles, and their place in the genetic regulatory hierarchy will be explored by means of gene expression studies, genetic epistasis analysis, functional studies using RNA interference, and lipid analysis. An extensive collection of mutants, together with the powerful genetic and genomic resources available in C. elegans, will allow rapid functional assessment of molecules regulating fat storage and lead to a better understanding of their interactions with other fat regulatory pathways. PUBLIC HEALTH RELEVANCE: Studies of fat storage regulation in C. elegans will identify key target genes that modulate fat storage in response to conserved transcriptional regulators and signal transduction pathways. New insights into the mechanisms controlling fat storage will contribute to a broader understanding of the causes and potential treatments of obesity and diabetes.