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

描述(申请人提供)：线虫脂肪储存和代谢的遗传学和基因组研究。肥胖困扰着数以百万计的世界公民。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护理提出了挑战。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抵抗肥胖的机制。我们在模式生物秀丽隐杆线虫中的工作导致了对脂类稳态保守调节器的鉴定。这些研究的中心假设是，脂肪储存的变化是调控途径和下游脂肪代谢基因相互作用的结果。这项拨款建议识别关键的转录调控基因NHR-和DAF-16/FOXO下游的脂肪调节和脂肪调节基因。将通过基因表达研究、遗传上位性分析、使用RNA干扰的功能研究和脂类分析来探索脂类调节剂的鉴定、它们的功能作用以及它们在遗传调控层级中的位置。广泛的突变体集合，加上线虫强大的遗传和基因组资源，将使人们能够快速评估调节脂肪储存的分子的功能，并更好地了解它们与其他脂肪调节途径的相互作用。 与公共健康相关：线虫脂肪储存调节的研究将确定调节脂肪储存的关键靶基因，以响应保守的转录调节和信号转导途径。对脂肪储存控制机制的新见解将有助于更广泛地了解肥胖和糖尿病的原因和潜在的治疗方法。

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.