Molecular Basis for Aquaporin Conductance

描述（由申请人提供）：水通道蛋白（AQP）是一种主要类型的整合膜蛋白，存在于生命的所有领域，可选择性地跨膜转运水和/或脂肪醇和氨。在人类中有13种AQPs表现出组织特异性表达。水通道蛋白功能的缺陷与许多人类疾病有关，包括肾功能障碍、脑水肿和视力丧失。脑水肿本身是与许多常见神经系统疾病相关的死亡率和发病率的重要因素。事实上，通过主动转运产生的跨细胞膜的电化学梯度的破坏对细胞活力是非常破坏性的。因此，了解水通道蛋白如何发挥功能的分子基础是水通道蛋白群体的一个关键目标。拟议研究的目标是了解水通道蛋白如何能够在保持这种电化学膜电位的同时，以接近扩散速率将水转运穿过细胞膜。AQPZ，两个水通道蛋白之一，从大肠杆菌的突变研究，将被用来解决这个问题。我还建议促进抑制剂的发现，是选择性的一个特定的水通道蛋白是关键的红细胞形式的恶性疟原虫。用治疗剂靶向AQP可能成为对抗疾病的有价值的途径。

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.