Bunimovich, Yuri and Kagan, Valerian and Saxena, Sunil
(2020)
Deciphering Redox Free Radical Mechanisms of 15LOX/PEBP1-Driven Ferroptosis in Skin.
In: Pitt Momentum Fund 2020, University of Pittsburgh, Pittsburgh, Pa.
(Unpublished)
Abstract
This proposal will uncover critical molecular mechanisms governing a new class of death signaling pathway (ie ferroptosis) and its relevance to ultraviolet radiation (UVR)-induced skin injury and cutaneous malignancies. The team will focus on the key role played by protein 15-lipoxygenase (15-LOX) in ferroptosis using a broad interdisciplinary approach. Specifically the team will: (1) Elucidate the local structure around the catalytic site of 15-LOX as well as in a complex of 15-LOX with PEBP1 in order to understand how metal-protein interactions affect 15-LOX function and how PEBP1 binding to 15-LOX opens the active site; (2) Measure the atomic structure and molecular interactions of 15-LOX active site in the presence of newly designed specific inhibitors of 15-LOX/PEBP1 complex in order to understand the mechanism of inhibition; and (3) Characterize the previously unexplored role of 15-LOX/PEBP1 complex in triggering ferroptotic death of skin cells (melanocytes and keratinocytes) and its regulation by selective new inhibitors and melanin biosynthesis. The interdisciplinary team brings together the experts from the School of Arts and Sciences, the School of Medicine and the School of Public Health. The project builds on the expertise of the Kagan group in the discovery and understanding of the biochemical network that underpins ferroptosis. The Saxena group brings in the knowledgebase to measure at the atomic level key interactions that are essential for ferroptosis in order to aid the development of new ferroptosis inhibitors. Finally, the Bunimovich group will expand the mechanistic studies to skin cell models and will explore the relevance of ferroptosis and 15LOX/PEBP1 inhibition in dermatological diseases. Understanding the mechanisms and regulation of ferroptosis in the skin will be critical for the prevention and treatment of radiation and drug-induced skin injury, as well as inflammatory, autoimmune and neoplastic cutaneous diseases such as psoriasis, lupus and melanoma.
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