The Metabolism and Signaling of Oxidized Lipids

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The cell membranes contain molecules called lipids that can be oxidized either by reactions catalyzed by enzymes or by reactions that take place in the absence of enzymes and lead to lipid peroxides. Lipid peroxides undergo subsequent reactions that lead to lipid peroxidation (LPO) products. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Gregory Tochtrop to investigate how LPO products are metabolized in living systems, and further, how they can turn on and off key genes involved in their own metabolism. The results of this research provide insight into both the formation and transformation of LPO products. This work will allow for the training of students in interdisciplinary chemical biology that will include chemical synthesis, protein purification, enzymology, metabolic biochemistry, and the use of model systems to study metabolism. This project also includes the development of a "Careers in Chemistry" seminar series for undergraduates and graduate students in which the students explore different career opportunities and the implementation of an innovative approach to raise mental health awareness of graduate students during the orientation.While LPO products have been known for some time, this work represents a new theme in the field wherein the existence of LPO products is tightly regulated not through enzymatic production, but rather through catabolic control. The central argument of this proposal is that both the formation and elimination of LPO products are controlled processes and the pathways responsible for both the formation and elimination of LPO products are regulated through a unique combination of metabolism and gene regulation. The proposed experimental plan carefully defines the metabolic pathways that break down LPO products and the signaling pathways that allow LPO products to control the transcription of genes. More specifically, the research seeks to advance the understanding of LPO biology by (1) defining the fates of the LPO products derived from linoleic acid, and (2) studying the ability of LPO products to signal through the peroxisome proliferator-activated receptors transcription factors.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.