Grant: Discovery Grants Program - Individual

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.