Investigating an uncharacterized mitochondrial protein in cellular and hepatic physiology

PROJECT SUMMARY/ABSTRACT This proposal details a career training plan for Dr. Walter Chen, a neonatologist at UT Southwestern, to become an independent physician-scientist studying metabolic organelles and how they contribute to liver homeostasis and disease (e.g., inborn errors of metabolism [IEMs]). Dr. Chen received his M.D. and Ph.D. degrees from Harvard and MIT, respectively, and completed Pediatrics residency at Boston Children’s Hospital. He then completed his Neonatal-Perinatal Medicine fellowship at UT Southwestern. During his fellowship, Dr. Chen initiated his postdoctoral research under the mentorship of Dr. Ralph DeBerardinis at UT Southwestern. Dr. DeBerardinis is an internationally recognized expert in the study of human metabolism and IEMs using advanced metabolic techniques, such as stable isotope tracing. Dr. DeBerardinis has mentored numerous trainees, many of whom have become successful academic investigators. Under this award, Dr. Chen will be supported by Dr. DeBerardinis and a co-mentor Dr. Hao Zhu, who is an expert in liver biology. These mentors, as well a multidisciplinary advisory team, will provide scientific expertise and guidance that will facilitate Dr. Chen’s career development. In this proposal, Dr. Chen will learn stable isotope tracing techniques and how to use mouse models to study liver biology, which will be critical for his transition to independence. At UT Southwestern, Dr. Chen will have access to all the resources and expertise needed to conduct his research and develop as an independent investigator. This research proposal will investigate an uncharacterized mitochondrial protein in cellular and hepatic physiology that has connections to an IEM and is implicated in type 2 diabetes. Preliminary studies indicate that this protein regulates valine and isoleucine catabolism, an important metabolic pathway in the liver. Aim 1 will define the function and mechanism of action of this protein using cultured cells. Aim 2 will investigate the effects of losing this protein on core metabolic processes, such as mitochondrial respiration. Aim 3 will determine the role of this protein in hepatic physiology by studying liver-specific knockout mice. This work will elucidate the mechanism, function, and role of this uncharacterized mitochondrial protein in cellular and hepatic physiology, thus providing insights that will advance our understanding of how dysfunction of this protein can contribute to human disease. Through this award, Dr. Chen will develop the skills necessary to become an NIH-funded independent investigator.