The candidate received his PhD training in theoretical physics from the University of Chicago where he developed mathematical and computational tools to study physical systems that are disordered. After his PhD, he transitioned to the field of systems biology as a postdoctoral fellow in the laboratory of Professor Philippe Cluzel at Harvard University. During his postdoctoral work, the candidate has investigated mutations in protein coding sequences that do not change the encoded amino acid yet cause changes in protein expression. The candidate discovered in the bacterium, Escherichia coli, that such synonymous mutations can mediate over 100-fold differences in protein levels during amino acid limitation with little or no effect during nutrient-rich growth. Based on this finding, the candidate has hypothesized that synonymous codon choice is a significant determinant of protein levels during amino acid limitation. The goal of the proposed research is to determine the mechanistic basis and the physiological relevance of this hypothesis in two different model systems - bacteria and cancer cells. To achieve this goal, the candidate seeks training in molecular biology and genome- wide methods under the mentorship of Professor Erin O'Shea in the Department of Molecular and Cellular Biology at Harvard University. By combining this training with his prior experience in quantitative modeling, the candidate will acquire a comprehensive understanding of the role of synonymous mutations in regulation of protein expression during amino acid limited growth of bacteria and cancer cells. The long-term goal of the candidate's research is to understand how genetic information in a protein coding sequence modulates the synthesis rate of the corresponding protein during the response to different environmental cues. At the end of the mentored period, the candidate desires to pursue his long-term goal as an independent researcher at an academic institution.
Bacterial pathogens and cancer cells often face nutrient limitation in their natural environments. The proposed research will illuminate a mechanism of gene regulation during nutrient limitation that is based on the degenerate structure of the genetic code, and thus affects the expression of all proteins. Suppressing this mechanism using drugs might be a general and effective strategy to reduce the survival of bacterial pathogens and cancer cells in nutrient-poor environments.
|Subramaniam, Arvind R; Zid, Brian M; O'Shea, Erin K (2014) An integrated approach reveals regulatory controls on bacterial translation elongation. Cell 159:1200-11|