Control of fat accumulation in relation to cardiac function in Drosophila

描述(由申请人提供)： 肥胖极大地影响心脏功能，增加心脏病。尽管发生肥胖的遗传易感性的概念已经得到了很好的确立和记录，但参与调节脂肪代谢/肥胖的遗传网络及其相关的疾病风险仍然知之甚少。在了解衰老的遗传控制方面的许多最新进展源于对无脊椎动物模式生物的研究。同样，脂肪代谢和心脏功能之间的关系也可以在简单和遗传可及的果蝇模型系统中得到有效解决。苍蝇心脏最近已经成为一种很有前途的模型，不仅可以研究心脏发生的保守遗传网络，还可以研究建立和维持心脏功能的控制机制。这项建议的主要焦点是以果蝇为模型，深入了解控制脂肪代谢的遗传机制，因为它与心脏功能有关。我们建议使用突变或其他基因操纵的果蝇来评估心脏功能的变化与新陈代谢的变化。我们将检验这一假设，即脂代谢和储存的一些基因控制也会影响心脏功能，反之亦然。在一种方法中，我们将研究已知或怀疑与脂肪代谢和生长有关的候选基因。我们还将筛选同时影响脂肪和心脏功能的新突变。这项提议的目标是研究控制脂肪利用和心脏功能特征之间的遗传联系，使用苍蝇作为人类肥胖和心脏功能之间潜在相似(遗传)联系的原型。 在目标1中，我们计划研究生长和代谢的关键调节因子雷帕霉素(TOR)途径的靶点，它如何影响脂肪利用与心脏功能的关系。在目标2中，我们计划研究最近发现的和其他可能影响脂肪-心脏功能轴的候选基因，包括管状基因、脂肪酸转运体等)，以及它们与TOR信号的关系。在目标3中，我们计划对改变脂肪含量和心脏功能的突变进行平行筛选，目的是识别影响脂肪/心脏关系的新调节因素。这些努力的结果有望为脂肪堆积的复杂控制及其对心脏功能的影响提供关键的机制洞察

DESCRIPTION (provided by applicant): Obesity dramatically influences cardiac function and increases heart disease. Even though the concept of genetic predisposition for developing obesity is well established and documented, the genetic networks involved in regulating fat metabolism/obesity and its associated disease risks are still poorly understood. Many recent advances in understanding the genetic control of aging stem from studies in invertebrate model organisms. Similarly, the relationship between fat metabolism and heart function may also be productively addressed in the simple and genetically accessible model system of Drosophila. The fly heart has recently emerged as a promising model to study not only the conserved genetic network of cardiogenesis but also the control mechanisms that establish and maintain heart function. The main focus of this proposal is to gain insights into the genetic mechanisms that control fat metabolism as it is related to cardiac function using Drosophila as a model. We propose to assess alterations in heart function in parallel with metabolic changes using mutant and otherwise genetically manipulated flies. We will test the hypothesis that some of the genetic controls of lipid metabolism and storage also affect heart function and vice versa. In one approach, we will study candidate genes known or suspected to be involved lipid metabolism and growth. We will also screen for new mutants that affect both fat and cardiac function. The goal of this proposal is to study genetic links between the control of fat utilization and cardiac performance characteristics using the fly as a prototype for potentially similar (genetic) links between obesity and heart function in humans. In aim 1, we plan to study a key regulator of growth and metabolism, the Target of Rapamycin (TOR) pathway, how it affects fat utilization in relation to cardiac function. In aim 2, we plan to study recently identified and other candidate genes potentially influencing the fat-cardiac function axis, including tubby-like genes, fatty acid transporters, etc.), as well as their relationship to TOR signaling. In aim 3, we plan to carry out parallel screens for mutants that alter fat content and cardiac function with the goal of identifying new regulators influencing the fat/heart relationship. The outcome of these efforts is expected to provide key mechanistic insights into the complex control of fat accumulation and its influence on heart function