肾脏集合管水的重吸收决定着机体的水平衡，水通道蛋白AQP2通过转运而定位于顶端膜则介导了这一过程。在影响AQP2转运的机制中，细胞骨架有重要作用。我们新发现，一种骨架蛋白-原肌球调节蛋白1（Tmod1）在集合管特异表达，Tmod1+/-小鼠有尿浓缩障碍且AQP2胞膜定位减少。由此提出假说：Tmod1通过影响AQP2的转运而促进AQP2在顶端膜上的聚集，以增加集合管对水的重吸收，进而调节机体的水平衡稳态。我们拟利用Tmod1肾脏特异性敲除小鼠、代谢笼、分子生物学技术和蛋白质质谱技术，通过体内和体外实验，明确Tmod1在集合管水重吸收中发挥的作用；验证Tmod1通过影响AQP2的胞吐和/或胞吞，调节AQP2的定位和细胞对水的通透性；阐明Tmod1如何通过与其它蛋白的相互作用而调节AQP2的转运。本课题将加深人们对AQP2转运调节机制的理解，并为治疗以水平衡失调为特征的多种疾病提供新的药物靶点。

Water balance in human body is determined by water reabsorption of renal collecting duct, which is mediated by the targeting of aquaporin2 (AQP2) onto the apical membrane via trafficking. Among the mechanisms that regulate AQP2 trafficking, cytoskeleton plays an important role. Recently, we discovered that a cytoskeletal protein, Tropomodulin1 (Tmod1), was specifically expressed in collecting duct. Tmod1+/- mice display a defect in urine concentration and a decrease in membrane localization of AQP2. Based on literatures and these results, we hypothesize that Tmod1 enhances the water reabsorption of collecting duct and regulates the water homeostasis by affecting AQP2 trafficking and promoting its membrane accumulation. To test our hypothesis, we will create kidney-specific Tmod1 knockout mice and utilize metabolic cages, molecular biology techniques, and protein mass spectrometry, etc. By performing both in vivo and in vitro experiments, we are aimed to define the role of Tmod1 in water reabsorption of renal collecting duct; to investigate whether Tmod1 could regulate the cellular localization of AQP2 and water permeability of cells by affecting AQP2 exocytosis and / or endocytosis; to elucidate how Tmod1 regulates AQP2 trafficking by interacting with other proteins. Our project will enhance our understanding on the mechanisms that regulates AQP2 trafficking. It will also provide new targets for people to treat various diseases characterized by disordered water balance.