Signaling and transcriptional control of metabolic pathways in Drosophila

代谢营养物质如糖、脂肪和氨基酸的生化途径已在经典研究中阐明。激素在协调各种器官系统的活动以响应不同的饮食条件方面的影响也得到了深入的研究。相比之下，在多细胞生物体中，对调控酶的转录和信号机制的了解要少得多，而这些酶实际上执行特定的代谢程序。该建议使用果蝇作为遗传模型系统，重点关注参与脂肪和氨基酸分解的两组转录调节因子。一种是锌指转录因子，其被膳食糖激活，并在转录上抑制编码脂质和氨基酸分解代谢酶的基因。另一种是组蛋白乙酰化酶，它调节脂肪代谢，作为全球饥饿反应的一部分。我们将研究这些转录因子如何协调脂肪和氨基酸的分解，以及它们如何被保守的代谢传感器AMP激活的蛋白激酶（AMPK）和雷帕霉素靶（Tor）调节。这些研究在现代社会中尤其相关，其中饮食驱动的代谢紊乱已成为主要的健康问题。

Biochemical pathways that metabolize nutrients such as sugars, fats and amino acids have been elucidated in classical studies. The influence of hormones in coordinating the activities of various organ systems in response to different dietary conditions has also been intensely investigated. By contrast, much less is known in multicellular organisms about the transcriptional and signaling mechanisms that regulate enzymes that actually carry out specific metabolic programs. This proposal uses Drosophila as a genetic model system to focus on two groups of transcriptional regulators that are involved in fat and amino acid breakdown. One is a zinc-finger transcription factor that is activated by dietary sugar and which transcriptionally represses genes encoding lipid and amino acid catabolizing enzymes. The other is a histone acetylase that regulates fat metabolism as part of a global starvation response. We will study how these transcription factors coordinate fat and amino acid breakdown, and how they are modulated by the conserved metabolic sensors AMP-activated protein kinase (AMPK) and Target of rapamycin (Tor). These studies are especially relevant in modern societies where diet driven metabolic disturbances have become a major health concern.