CTP合成酶动态组装细胞蛇调控果蝇脂质代谢稳态的生理功能和机制

细胞内区域化对细胞代谢调控至关重要。2010年，申请人所在课题组首次报道合成核苷酸CTP的关键酶CTP合成酶（CTPS）在细胞内形成蛇状结构，这种结构从细菌到人类细胞高度保守。已知CTPS活性失调是许多种癌症的重要特征。然而，CTPS细胞蛇动态组装调控脂代谢的生理学功能鲜有报道。我们最新研究发现，果蝇脂肪体中CTPS细胞蛇在营养感知和脂质代谢调节中扮演重要角色。在前期研究基础上，本项目通过构建脂肪体CTPS功能获得或缺失果蝇模型，研究CTPS动态组装对脂代谢通路的调节功能，探讨CTPS细胞蛇组装异常引发代谢紊乱的生理学基础；基于TurboID介导临近蛋白标记技术，筛选鉴定与CTPS特异性互作的新颖蛋白；借助基因芯片分析技术，探寻受CTPS调控的靶基因。本项研究力图揭示果蝇体内CTPS的代谢调控作用与机制，为了解细胞蛇在脂肪细胞调控脂质稳态的功能和疾病防治提供分子层面的重要靶标。

Intracellular compartments such as organelles are essential for cellular function as they carry out many biological processes that are critical for the cells to live. CTP synthase (CTPS) forms snake-like structure, termed cytoophidium, which is highly conserved from bacterial to human. CTPS is frequently misregulated in cancer. However, little is known about the physiological function of CTPS in contoling lipid metabolism. Drosophila fat body, an organ that retains endocrine and storage functions of the vertebrate liver and adipose tissue. Drosophila is an ideal genetic model for studying the molecular basis of energy homeostasis and metabolic diseases, providing a unique approach to understand the physiological functions of CTPS cytoophidia in lipid homeostasis. Our previous studies indicate that CTPS may play a crucial role in metabolism in the fat-body of Drosophila melanogaster. Here using CRISPR/Cas9 system and UAS/GAL4 system technology, we intend to employ tissue specific gain- and lack-of-function approaches and explore the physiological mechanisms by which CTPS controls metabolic programs. In addition, using TurboID-mediated biotinylation coupled with mass spectrometry, we will characterize the proximate proteome of the cytoophidium to study the spatial and interaction characteristics of CTPS in adipocytes. Furthermore, using genome-wide analysis tools (such as RNA-seq analysis), we attempt to identify new target genes regulated by the CTPS in the control of lipid metabolism. Furthermore, we will also investigate the molecular mechnisms underlying dysregulation of lipid metabolismin in CTPS-mutant flies. This study will help dissect the molecular and physiological mechanisms for CTPS regulation of lipid metabolism in response to changes in energy demand and nuturient stresses, ultimately providing a new paradigm with respect to the molecular basis for the pathogenic progression of metabolic disorders.