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

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZDK1-GRB-2 (O1))
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Srinivas, Pothur R
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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