Pourmand Elham, Zhang Fan, Sarparast Morteza, Alan Jamie K, Lee Kin Sing Stephen
Department of Chemistry, Michigan State University, East Lansing, MI, USA.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
bioRxiv. 2023 Oct 3:2023.10.02.560544. doi: 10.1101/2023.10.02.560544.
Aging is one of the major risk factors for many chronic diseases, including diabetes, neuropathy, hypertension, cancer, and neurodegenerative diseases. However, the mechanism behind aging and how aging affects a variety of disease progression remains unknown. Recent research demonstrated the cytochrome P450 (CYP)-epoxide hydrolase (EH) metabolites of polyunsaturated fatty acids (PUFAs) play a critical role in the abovementioned age-associated diseases. Therefore, aging could affect the abovementioned chronic diseases by modulating CYP-EH PUFA metabolism. Unfortunately, investigating how aging affects CYP-EH metabolism in human and mammalian models poses significant challenges. In this regard, we will use as a model organism to investigate the aging effects on CYP-EH metabolism of PUFA, owing to its long history of being used to study aging and its associated benefits of conducting aging research. This project will develop analytical tools to measure the endogenous levels of CYP-EH PUFA metabolites in using state-of-the-art ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). These metabolites are very potent but present in low abundance. The dramatic increase in sensitivity in UPLC-MS/MS allows us to monitor these metabolites over the lifespan of C. with minimum samples. Our results show that produces similar CYP PUFA metabolites to mammals and humans using our SPE-UPLC-MS/MS method. We will also show that our method successfully determined the CYP-EH PUFA metabolites profile changes induced by the inhibition of EH. The method developed from this project will significantly improve our understanding of the role of dietary PUFAs and associated metabolism on aging and neurodegeneration and will uncover new mechanisms of how aging affects neurodegeneration through the modulation of PUFA metabolic pathways.
衰老 是许多慢性疾病的主要风险因素之一，包括糖尿病、神经病变、高血压、癌症和神经退行性疾病。然而，衰老背后的机制以及衰老如何影响各种疾病的进展仍然未知。最近的研究表明，多不饱和脂肪酸（PUFA）的细胞色素P450（CYP）-环氧化物水解酶（EH）代谢产物在上述与年龄相关的疾病中起关键作用。因此，衰老可能通过调节CYP-EH 多不饱和脂肪酸代谢来影响上述慢性疾病。不幸的是，在人类和哺乳动物模型中研究衰老如何影响CYP-EH代谢面临重大挑战。在这方面，我们将使用 作为模式生物来研究衰老对PUFA的CYP-EH代谢的影响，这是由于其长期用于研究衰老以及进行衰老研究的相关优势。该项目将开发分析工具，使用最先进的超高效液相色谱-串联质谱（UPLC-MS/MS）来测量 中CYP-EH PUFA代谢产物的内源性水平。这些代谢产物非常有效，但含量很低。UPLC-MS/MS灵敏度的显著提高使我们能够在最少的样本情况下监测 整个生命周期内的这些代谢产物。我们的结果表明，使用我们的SPE-UPLC-MS/MS方法， 产生的CYP 多不饱和脂肪酸代谢产物与哺乳动物和人类相似。我们还将表明，我们的方法成功地确定了由 EH抑制引起的CYP-EH PUFA代谢产物谱的变化。从这个项目中开发的方法将显著提高我们对膳食多不饱和脂肪酸及其相关代谢在衰老和神经退行性变中的作用的理解，并将揭示衰老如何通过调节多不饱和脂肪酸代谢途径影响神经退行性变的新机制。
