Molecular Genetics of Lipid Metabolism

描述（由申请人提供）：在过去的几十年里，肥胖已经成为一个世界性的健康问题。其并发症对个人和社会都是代价高昂的。迫切需要鉴定用于改善肥胖症如2型糖尿病、高脂血症和非酒精性脂肪性肝病的代谢后果的新药物靶标。 肥胖及其伴随疾病需要更多了解的一个核心方面是，在这种情况下，生物体如何安全地储存在全身积累的多余脂质。过去十年的研究表明，脂肪组织是一个“容量有限的电池”，多余的脂质溢出到其他组织和器官会加重疾病负担。该申请旨在通过响应NIH的“增强斑马鱼研究的遗传筛选（R01）”资助机会来解决对抗肥胖及其相关疾病的新药靶标的需求。提出了一项在斑马鱼中进行大规模正向遗传筛查的建议，重点是肝脏脂肪变性（肝脏中多余的脂质）和脂肪量的改变。我们提供了初步的数据，强调在这个模型生物体中研究脂质代谢的可行性，并确定和表征完全新颖的和潜在的可药用的能量代谢节点。我们证明了广泛的方法，包括分子遗传学，整体动物生理学，营养学，生物化学，电生理学和显微镜技术，可以成功地应用于研究突变体，我们打算在这次筛选中分离，希望 对单个基因的突变如何引起复杂的代谢表型有了全面的认识。

DESCRIPTION (provided by applicant): Obesity has emerged as a world-wide health problem over the past several decades. Its complications are costly on individual and societal levels. There is urgent need to identify new drug targets for ameliorating the metabolic consequences of obesity such as type 2 diabetes mellitus, hyperlipidemia, and non-alcoholic fatty liver disease. One central aspect of obesity and its attendant illnesses that requires greater understanding is how the organism can safely store the excess lipids that accumulate throughout the body in this condition. Work over the past decade has revealed that the adipose tissue is a "battery of finite capacity," and that spill-over of lipid surplus into other tissues and organs contributes to diseas burden. This application seeks to address the need for new drug targets to combat obesity and its related illnesses by responding to the NIH's "Genetic Screens to Enhance Zebrafish Research (R01)" Funding Opportunity. A proposal to perform a large-scale forward genetic screen in zebrafish for lipid metabolic phenotypes, with a focus on hepatic steatosis (excess lipids in the liver) and altered adipose mass, is presented. We provide preliminary data underscoring both the feasibility of studying lipid metabolism in this model organism, and for identifying and characterizing completely novel and potentially druggable nodes of energy metabolism. We demonstrate that a wide-range of methods including molecular genetic, whole-animal physiologic, nutritional, biochemical, electrophysiologic, and microscopic techniques can be successfully applied to the study of mutants we intend to isolate in this screen in the hopes of arriving at a comprehensive view of how mutation of a single gene can give rise to complex metabolic phenotypes.