Comparative studies of mitochondrial uncoupling proteins

哺乳动物线粒体解偶联蛋白(UCPs)是本研究的重点。这些耐人寻味的蛋白质位于哺乳动物组织线粒体的内膜，作为抗氧化剂，将呼吸(氧化过程)与ATP合成分离。线粒体是三磷酸腺苷的主要生产者，三磷酸腺苷是维持生命的细胞能量的来源。矛盾的是，线粒体也是过量活性氧(ROS)的重要来源，ROS对线粒体和细胞都是有害的。线粒体功能受损被认为是神经系统退行性疾病(如阿尔茨海默氏症和帕金森氏病)、脑损伤后创伤后死亡和衰老的主要原因之一。人们普遍认为，UCPs可以通过其解偶联功能减少ROS的产生。除了在氧化应激反应中的治疗作用外，它们还参与了糖尿病、炎症过程和抗肥胖机制的激活。尽管有这些重要的生理功能，除了其中一种蛋白质UCP1在幼年哺乳动物体内调节体温方面的既定作用外，关于UCPs的生物学功能的结构和机制的信息还很有限。对UCPs的各种生理作用的详细研究对于理解哺乳动物细胞系统中健康和疾病的生物学是必要的，而且可能具有重要意义。拟议的研究计划将推进我实验室现有的成熟研究计划，并将专注于探索线粒体模型膜中解偶联蛋白的结构及其作为主要生物学功能的质子和阴离子运输机制。该研究计划是跨学科的，将不同的结构分析方法与合成、光谱、电生理和分子建模技术相结合，以探索UCPs结构与功能关系的生物物理基础。这一UCPs的分子研究结果可能对开发治疗和医学应用具有重要意义。

Mammalian mitochondrial uncoupling proteins (UCPs) are the focus of this research program. These intriguing proteins are located in the inner membrane of the mitochondria of mammalian tissues and, acting as antioxidants, uncouple the respiration (oxidative processes) from the ATP synthesis. Mitochondria are the main producers of ATP, which is the source of cellular energy for maintenance of life. Paradoxically, mitochondria are also important sources of excessive reactive oxygen species (ROS), which are deleterious to both mitochondria and cells. Damaged dysfunctional mitochondria are considered to be one of the main causes of degenerative diseases of the nervous system (such as Alzheimer's and Parkinson's diseases), post-traumatic death after brain injury and ageing. It has been widely suggested that UCPs can reduce ROS production through their uncoupling function. In addition to the therapeutic role of UCPs in response to oxidative stress, their involvement in diabetes, inflammatory processes and activation of anti-obesity mechanism have been suggested. Despite these important physiological roles, and apart from the established role of one of these proteins, UCP1, in regulating the body temperature in young mammals, only limited information has been documented on the structures and mechanism of the biological function of UCPs. A detailed study of the diverse physiological roles of UCPs is necessary and likely to be significant in understanding the biology of health and disease in mammalian cellular systems. The proposed research program will advance an existing well-established research program in my laboratory and will concentrate on exploring the structure of the uncoupling proteins in mitochondrial model membranes and their mechanism of proton and anion transport as their principal biological function. The research program is interdisciplinary, and combines different methods of structural analysis with synthetic, spectroscopic, electrophysiological and molecular modeling techniques to explore the biophysical basis of the structure-function relationships in the UCPs. The results of this molecular study of UCPs can have important implications for the development of therapeutic and medical applications.