Tuesday, May 14, 2024
5/14/2024
PROJECT SUMMARY/ABSTRACT This is an F31 application from Robert Hall, who is a predoctoral student in the Department of Pharmacology and Chemical Biology at University of Pittsburgh School of Medicine, under the mentorship of Drs. Adam Straub and Patrick Pagano. This project focuses on ferroptosis, an iron-dependent form of cell death initiated by intracellular iron (Fe2+) accumulation and elevated hydrogen peroxide (H2O2) levels, which leads to polyunsaturated fatty acids (PUFAs) peroxidation and cell death. Emerging evidence supports the concept that ferroptosis contributes to endothelial cell (EC) dysfunction and the development of several cardiovascular diseases. However, the mechanisms modulating ferroptosis in ECs are not fully elucidated. The Straub lab focuses on understanding the physiological and pathophysiological roles of cytochrome b5 reductase (CYB5R 1-5) enzymes in the cardiovascular system, which are proteins that govern redox balance. We recently conducted a large-scale genomic screen comparing differences gene profiles from all five CYB5R enzymes knocked down in primary human aortic endothelial cells (HAECs). Pathway analysis revealed that loss of CYB5R1 increased ferroptosis-related genes. Preliminary studies demonstrates that CYB5R1 localizes to the outer mitochondrial membrane and functions to mitigate the accumulation of ROS and lipid peroxides, ultimately preventing ferroptosis. Based on our preliminary data we hypothesize than CYB5R1 protects endothelial cells from ferroptotic cell death by mitigating membrane lipid peroxidation. We will test this hypothesis using two specific aims. Aim 1 will determine the mechanism by which endothelial CYB5R1 modulates ferroptosis and Aim 2 will determine whether loss of endothelial cell expressed CYB5R1 impacts blood vessel function. These studies will help define a potential new role of CYB5R1 in endothelial cell function, with particular focus on ferroptosis. Importantly, this project, coupled with didactic coursework, mentored training, and a customized career development plan within an exceptional training environment at the University of Pittsburgh, will ultimately provide the necessary skill sets needed to help foster the applicant’s long-term goal of a career in biomedical research.
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