Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY Low chronic inflammation is a hallmark of aging. The arachidonic signaling cascade is arguably one of the most important lipid signaling pathways in inflammation. It consists of three branches that are defined by their key lipid-modifying enzymes called cyclooxygenases (COX), lipoxygenases (LOX) or epoxygenases, a group of cytochrome P450 type enzymes (CYP). The COX and LOX branches are fairly well understood while the CYP branch remains largely unexplored. It signals through epoxyeicosatrienoic acids, epoxides generated through the oxidation of fatty acids by CYP epoxygenases. The lifetime of these epoxides is controlled by a soluble epoxide hydrolase (sEH) through hydrolysis. In mammals, pharmacological inhibition of sEH leads to wide-ranging benefits, particularly in the context of diabetes, improving metabolic function and preventing complications like neuropathy. These beneficial effects imply the existence of an endogenous epoxide that accumulates upon inhibition of sEH. However, neither the CYP epoxygenase nor the endogenous epoxide mediating the beneficial effects of sEH inhibition have been identified. In chemical screens for compounds that extend C. elegans lifespan, we identified inhibitors that target the sEH homolog of C. elegans to extend lifespan. Our data suggest that the accumulation of an unknown endogenous epoxide, produced in the CYP branch of the arachidonic signaling cascade, promotes tissue health and survival by an ancient evolutionarily conserved lipid signaling mechanism. In this current application, we propose to elucidate the major components of the CYP branch in C. elegans to gain insight on how it modulates aging and how it links aging to inflammation at the molecular level.
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