The Metabolism and Signaling of Oxidized Lipids

细胞膜含有被称为脂类的分子，可以通过酶催化的反应或在没有酶的情况下发生的反应来氧化，从而导致脂质过氧化。过氧化脂质发生后续反应，产生过氧化脂质(LPO)。通过这一奖项，化学部生命过程化学项目资助Gregory Tochtrop博士研究LPO产品如何在生命系统中代谢，以及它们如何打开和关闭与自身新陈代谢相关的关键基因。这项研究的结果为LPO产品的形成和转化提供了洞察力。这项工作将允许对学生进行跨学科化学生物学的培训，包括化学合成、蛋白质纯化、酶学、代谢生物化学，以及使用模型系统来研究新陈代谢。该项目还包括为本科生和研究生开发“化学职业”系列研讨会，让学生探索不同的职业机会，并实施创新方法，以提高研究生在定向期间的心理健康意识。虽然LPO产品已为人所知已有一段时间，但这项工作代表了该领域的一个新主题，在该领域，LPO产品的存在不是通过酶生产而是通过分解代谢控制来严格调控的。这一建议的中心论点是，LPO产物的形成和消除都是受控过程，负责LPO产物形成和消除的途径是通过代谢和基因调控的独特组合来调节的。拟议的实验计划仔细定义了分解LPO产物的代谢途径，以及允许LPO产物控制基因转录的信号途径。更具体地说，这项研究试图通过(1)定义亚油酸衍生的LPO产品的命运，以及(2)研究LPO产品通过过氧化物体增殖物激活受体转录因子发出信号的能力，以促进对LPO生物学的理解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.