Pgant4-Tango1-ER/Golgi 通路对缺氧耐受能力的调节作用及机制研究

A large number of pathogenesis and clinical trial studies for ischemia-induced injury and protection failed to develop effective drugs; it calls for the discovery of unknown mechanisms underlying the hypoxia-induced injury. We conducted an unbiased genetic screen and obtained some mutants with increased hypoxia tolerance, one of which was Pgant4 (an O-glycosyltransferase) mutant. The substrate of Pgant4 is Tango1 protein that is required for the formation of a special protein sorting/transport vesicle on the ER/Golgi pathway. We also found that the Tango1 level was increased during hypoxia in a time-dependent fashion.Down-regulation of Tango1 also significantly inhibited neuronal apoptosis induced by hypoxia and increased hypoxia tolerance, while expression of Tango1 produced the opposite effect. .This study will:1) further clarify the role of Pgant4 and Tango1 in hypoxia injury in Drosophila, cultured mammalian cells and mouse hypoxia models; 2) examine the regulation of Tango1 by Pgant4, and the changes in the formation and transported of Tango1-containing vesicles. This study is expected to reveal the role of Pgant4-Tango1- ER/Golgi pathway in hypoxia-induced injury, a potential novel pathological mechanism for hypoxia injury, and to provide a novel therapeutic target for stroke.

尽管对缺氧损伤进行了长期大量的病理机制研究和治疗试验，但还没有有效的药物，可能是一些重要的分子细胞机制还未被揭示。因此，我们前期利用果蝇进行了无偏倚的（unbiased）遗传筛选，得到了一些缺氧耐受能增强的突变体。其中之一是糖基转移酶Pgant4的突变体。Pgant4的底物是Tango1蛋白, Tango1在ER/Golgi通路中介导一种特异的分泌囊泡形成的。我们还发现Tango1表达量在缺氧后呈现时间依赖性上调，并且Tango1突变也显著抑制缺氧引起的神经元凋亡并提高果蝇存活率，而过量表达则产生相反的效果。本课题将在果蝇、培养细胞和小鼠缺氧损伤模型上进一步明确Pgant4和Tango1在缺氧损伤中作用、Pgant4对Tango1的调节以及Tango1介导的分泌囊泡的变化，明确Pgant4-->Tango1--> ER/Golgi通路在缺氧损伤中的作用。

尽管对缺氧损伤进行了长期大量的病理机制研究和治疗试验，但还没有有效的药物，可能是一些重要的分子细胞机制还未被揭示。因此，我们前期利用果蝇进行了无偏倚的（unbiased）遗传筛选，得到了一些缺氧耐受能增强的突变体。其中之一是糖基转移酶Pgant4的突变体。Pgant4的底物是Tango1蛋白, Tango1在ER/Golgi通路中介导一种特异的分泌囊泡形成的。我们还发现Tango1表达量在缺氧后呈现时间依赖性上调，并且Tango1突变也显著抑制缺氧引起的神经元凋亡并提高果蝇存活率，而过量表达则产生相反的效果。本课题将在果蝇、培养细胞和小鼠缺氧损伤模型上进一步明确Pgant4和Tango1在缺氧损伤中作用、Pgant4对Tango1的调节以及Tango1介导的分泌囊泡的变化，明确Pgant4-->Tango1--> ER/Golgi通路在缺氧损伤中的作用。