Molecular Basis for Aquaporin Conductance

描述（由申请人提供）：水通道蛋白（AQPs）是一类主要的完整膜蛋白，存在于生命的所有领域，选择性地跨膜运输水和/或脂肪醇和氨。人类有13种aqp表现出组织特异性表达。水通道蛋白功能缺陷与多种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，通过主动运输而产生的跨细胞膜电化学梯度的破坏对细胞活力是非常具有破坏性的。因此，了解AQPs功能的分子基础是水通道蛋白群落的一个关键目标。拟议研究的目标是了解AQPs如何能够以接近扩散速率将水输送到细胞膜上，同时保持这种电化学膜电位。来自大肠杆菌的两种水通道蛋白之一AQPZ的突变研究将用于解决这个问题。我还建议促进对一种特定AQP的选择性抑制剂的发现，这种AQP是恶性疟原虫红细胞形式的关键。靶向aqp的治疗方法可能成为对抗疾病的宝贵途径。

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.