Molecular Genetics of Lipid Metabolism

描述(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。它的复杂性在个人和社会层面上代价高昂。迫切需要确定新的药物靶点来改善肥胖的代谢后果，如2型糖尿病、高脂血症和非酒精性脂肪性肝病。 肥胖及其伴随的疾病的一个中心方面需要更多的了解，那就是在这种情况下，生物体如何安全地储存在全身积累的多余脂肪。过去十年的研究表明，脂肪组织是一个“容量有限的电池”，脂肪过剩溢出到其他组织和器官会增加疾病的负担。这项申请旨在通过响应美国国立卫生研究院的“基因筛查以加强斑马鱼研究(R01)”的资助机会，来解决对抗肥胖及其相关疾病的新药靶标的需求。建议在斑马鱼中进行大规模的脂肪代谢表型的正向遗传筛查，重点是肝脏脂肪变性(肝脏中过多的脂肪)和脂肪质量的改变。我们提供的初步数据强调了在这种模式生物中研究脂代谢的可行性，并用于识别和表征全新的和潜在的可用药的能量代谢节点。我们展示了广泛的方法，包括分子遗传学、全动物生理学、营养学、生化、电生理学和显微技术，可以成功地应用于我们打算在这一筛选中分离的突变体的研究，以期 对单个基因的突变如何导致复杂的代谢表型有一个全面的认识。

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.