果蝇脂肪体中内质网应激IRE1通路的代谢调控作用与机制

Chronic activation of endoplasmic reticulum (ER) stress is closely linked to dysregulation of sugar and lipid metabolism, and is implicated in human metabolic diseases. ER stress initiates the cellular unfolded protein response (UPR). ER-localized transmembrane kinase/RNase IRE1 (inositol-requiring enzyme 1) mediates a key signaling branch of the UPR, which is highly conserved from invertebrates to mammals. 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 IRE1 in carbohydrate and lipid homeostasis. Our previous studies indicate that IRE1 may play a crucial role in metabolism in the fat body of Drosophila melanogaster. Here using the UAS/Gal4 system with RNAi (interference) technology, we intend to employ tissue specific gain- and lack-of-function approaches and explore the physiological mechanisms by which IRE1 controls metabolic programs. In addition, using genome-wide analysis tools (such as microarray analysis), we attempt to identify new target genes regulated by the IRE1 pathway and elucidate XBP1-depentent or -independent actions in the control of glucose and lipid metabolism. Furthermore, we will also investigate the molecular mechnisms underlying dysregulation of sugar and lipid metabolismin in IRE1-mutant flies. This study will help dissect the molecular and physiological mechanisms for IRE1 regulation of sugar and 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.

内质网应激与糖脂代谢紊乱在机制上密切相关。内质网跨膜蛋白IRE1在内质网应激中介导一支进化上高度保守的关键信号通路。利用果蝇模式生物系统，探索IRE1通路调控糖脂代谢的生理学功能和机制，可以为解析内质网应激在代谢紊乱中的机制作用提供独特的视角。我们前期研究提示，果蝇脂肪体中IRE1在代谢调节中扮演至关重要的角色。本项目利用UAS/Gal4系统和RNAi技术，建立脂肪体IRE1功能获得或缺失模型，研究IRE1对糖脂代谢通路的调节功能；借助基因芯片分析技术，探寻受IRE1通路调控的靶基因，确定通过依赖或不依赖于下游XBP1实施代谢调控的信号机制；同时构建IRE1突变果蝇模型，探讨IRE1调节失控引发代谢紊乱的生理学基础。本项研究力图揭示果蝇体内IRE1通路的代谢调控作用与机制，将深化对内质网应激在生物学功能上的认知，为深入了解糖脂代谢紊乱疾病的发病机理提供新颖的生理学线索。

内质网中蛋白质稳态失衡引发内质网应激，激活未折叠蛋白反应。错误折叠蛋白的非正常聚集是神经退行性疾病包括帕金森疾病的重要特征。内质网应激与糖脂代谢紊乱在机制上密切相关。内质网跨膜蛋白IRE1在内质网应激中介导一支进化上高度保守的关键信号通路。利用果蝇模式生物系统，探索IRE1通路调控糖脂代谢和神经细胞命运决定的生理学功能和机制，可以为解析内质网应激在代谢紊乱和神经退行性疾病中的机制作用提供独特的视角。我们研究揭示了IRE1调节果蝇体内脂质稳态的新的调控机制。发现饥饿诱发IRE1激活，脂肪体内特异性抑制IRE1增强脂质动员和饥饿敏感性。反之，过表达IRE1则表型相反。遗传和生化分析揭示了IRE1通过XBP1调节FoxO降解进而抑制下游靶基因Brummer的表达。阐明了Ire1 作为代谢感应器通过Xbp1-FoxO通路阻止饥饿引发的脂解响应。.同时，我们发现果蝇视神经中α-synuclein 积累导致IRE1磷酸化激活。深入研究发现IRE1过表达后通过JNK，而不依赖XBP1的方式引发自噬性神经元死亡。发现果蝇中接头蛋白RACK1抑制IRE1活性。深入研究发现IRE1激活导致多巴胺神经元减少，运动能力下降，寿命缩短。在α-synuclein引发的帕金森疾病模型中，抑制IRE1或ATG7的表达显著减缓神经退行性病变的发生。这些体内证据阐明了IRE1激活状态的内质网应激通过诱导自噬性死亡促进帕金森疾病的发生发展。