Molecular Basis for Aquaporin Conductance

描述(由申请人提供)：水通道蛋白(AQPs)是一种主要的膜蛋白，存在于生命的各个领域，它选择性地跨膜转运水和/或脂肪醇和氨。在人类中，有13种水通道蛋白表现出组织特异性表达。水通道蛋白功能缺陷与许多不同的人类疾病有关，包括肾功能障碍、脑水肿和视力丧失。脑水肿本身是导致许多常见神经疾病的死亡率和发病率的重要因素。事实上，通过主动运输产生的跨细胞膜的电化学梯度的破坏，对细胞的生存能力是非常不利的。因此，了解水通道蛋白如何发挥作用的分子基础是水通道蛋白社区的一个关键目标。拟议研究的目的是了解水通道蛋白如何在保持电化学膜电位的同时，以接近扩散的速度在细胞膜上传输水。对AQPZ的突变研究将用于解决这个问题。AQPZ是来自大肠杆菌的两种水通道蛋白之一。我还建议促进对特定水通道蛋白具有选择性的抑制剂的发现，水通道蛋白是恶性疟原虫红细胞形式的关键。以水通道蛋白为靶点的疗法可能成为抗击疾病的一种有价值的途径。

DESCRIPTION (provided by applicant): Aquaporins (AQPs), a major class of integral membrane proteins found throughout all domains of life, selectively transport water and/or aliphatic alcohols and ammonia across membranes. There are 13 AQPs in humans that exhibit tissue specific expression. Defects in aquaporin function have been linked to a disparate number of human ailments including kidney dysfunction, brain oedema and vision loss. Brain oedema itself is a significant contributor to mortality and morbidity associated with many common neurological disorders. Indeed, disruption of the electrochemical gradient across the cell membranes, generated through active transport, is very disruptive to cellular viability. Thus, understanding the molecular basis for how AQPs function is a key objective within the aquaporin community. The goal of the proposed studies is to understand how AQPs are able to transport water across cellular membranes at near diffusion rates while preserving this electrochemical membrane potential. Mutational studies of AQPZ, one of two aquaporins from Escherichia coli, will be used to address this question. I also propose to facilitate the discovery of inhibitors that are selective for a particular AQP that is key to the red blood cell form of Plasmodium falciparum. Targeting AQPs with therapeutics may become a valuable avenue for combating disease.