Comparative studies of mitochondrial uncoupling proteins

线粒体解偶联蛋白的比较研究

• 批准号: 250119-2011
• 负责人: JelokhaniNiaraki, Masoud
• 金额: $ 2.91万
• 依托单位: Wilfrid Laurier University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=524930
• 关键词: Comparative; studies; mitochondrial; uncoupling; proteins

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.

哺乳动物线粒体解偶联蛋白（UCPs）是该研究计划的重点。这些有趣的蛋白质位于哺乳动物组织线粒体的内膜中，作为抗氧化剂，将呼吸（氧化过程）与ATP合成解偶联。线粒体是ATP的主要生产者，ATP是维持生命的细胞能量来源。特别地，线粒体也是过量活性氧（ROS）的重要来源，其对线粒体和细胞都有害。受损的功能障碍性线粒体被认为是神经系统退行性疾病（如阿尔茨海默病和帕金森病）、脑损伤后创伤后死亡和衰老的主要原因之一。它已被广泛认为，UCPs可以通过其解偶联功能减少ROS的产生。除了UCPs对氧化应激反应的治疗作用外，它们还参与糖尿病、炎症过程和抗肥胖机制的激活。尽管这些重要的生理作用，除了这些蛋白质之一，UCP 1，在调节体温在年轻的哺乳动物中的既定作用，只有有限的信息已被记录的结构和机制的生物功能的UCPs。详细研究UCPs的各种生理作用是必要的，可能对理解哺乳动物细胞系统中的健康和疾病生物学具有重要意义。拟议的研究计划将推进我的实验室现有的完善的研究计划，并将集中于探索线粒体模型膜中的解偶联蛋白的结构及其质子和阴离子转运机制作为其主要的生物学功能。该研究计划是跨学科的，并结合了不同的结构分析方法与合成，光谱，电生理和分子建模技术，以探索在UCPs的结构-功能关系的生物物理基础。UCPs的分子研究结果对治疗和医学应用的发展具有重要意义。