Investigating the differential effects of LPS toward cardiac mitochondria in young and aged mice

研究 LPS 对年轻和老年小鼠心脏线粒体的不同影响

• 批准号: RGPIN-2018-05696
• 负责人: Seubert, John
• 金额: $ 2.91万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=713823
• 关键词: Investigating; differential; effects; LPS; toward

OVERVIEW: Aging is a natural process involving the progressive decline in biological systems, such as mitochondrial structure and function. Many exogenous factors over a lifetime can impact mitochondria quality including exposure to environmental toxins like lipopolysaccharide (LPS). It is predicted there is an increased susceptibility to mitochondrial damage with age. However, the effect of chronic stressors on mitochondrial quality and the subsequent impact of aging is unknown. My research has been interested in studying long-chain n-3 and n-6 polyunsaturated fatty acids (PUFA) within the heart. These fatty acids are required components of phospholipid membranes and serve as precursors to a large family of eicosanoids. The metabolism of n-3 and n-6 PUFA occurs through three primary enzymatic systems cyclooxygenases (COX), lipoxygenases (LOX) and cytochrome P450 (CYP) enzymes generating a plethora of bioactive eicosanoids. Many of the eicosanoids are produced in response to inflammation; however, the biological activity of many of these metabolites, notably within the heart, remains largely unexplored and unknown. Our preliminary data suggest LPS triggers increased production CYP-derived metabolites of linoleic acid, which decrease mitochondrial quality. OBJECTIVES: The objective of my NSERC program is to discover novel and fundamental roles for bioactive lipid mediators produced endogenously within the heart. The focus of the current proposal is to explore the effect of low-grade chronic inflammation caused by LPS toward cardiac mitochondrial quality and how this changes in an aged heart. We propose that increased production of detrimental lipid mediators play a critical role in regulating mitochondrial quality contributing to an aged cardiac phenotype. The proposed research will (1) establish the time course and characterization of an eicosanoid profile, mitochondrial quality and cardiac function in young and aged mice exposed to chronic low doses of LPS; (2) evaluate the role of bioactive lipid mediators in regulating mitochondrial quality; and (3) explore the effect of a germ-free environment on cardiac function and mitochondrial during aging. Axenic (germ-free) mice together with a germ-free environment will be utilized to dissect out interactions between the host and LPS. This approach will allow us to explore basic mechanisms of how environmental toxins impact eicosanoid profiles and mitochondrial quality as well some fundamental insight into unique processes of biological aging isolated from microflora. SIGNIFICANCE: This work will increase our knowledge of endogenously produced lipid mediators and identify novel roles they have in regulating mitochondria in young and aged hearts. As well provide insight into understanding how chronic low-grade inflammation will alter eicosanoid profiles and effect mitochondria while investigating the impact of aging.

概述：衰老是一个自然过程，涉及生物系统的逐渐衰退，例如线粒体结构和功能。一生中的许多外源因素都会影响线粒体质量，包括暴露于脂多糖 (LPS) 等环境毒素。据预测，随着年龄的增长，线粒体损伤的敏感性会增加。然而，慢性应激源对线粒体质量的影响以及随后的衰老影响尚不清楚。我的研究兴趣是研究心脏内的长链 n-3 和 n-6 多不饱和脂肪酸 (PUFA)。这些脂肪酸是磷脂膜所需的成分，并且是类二十烷酸大家族的前体。 n-3 和 n-6 PUFA 的代谢通过三个主要酶系统进行，即环氧合酶 (COX)、脂氧合酶 (LOX) 和细胞色素 P450 (CYP) 酶，产生大量具有生物活性的类二十烷酸。许多类二十烷酸是因炎症反应而产生的。然而，许多这些代谢物的生物活性，特别是在心脏内，在很大程度上仍未被探索和未知。我们的初步数据表明，LPS 会引发 CYP 衍生的亚油酸代谢产物的产生增加，从而降低线粒体质量。 目标：我的 NSERC 项目的目标是发现心脏内源性产生的生物活性脂质介质的新颖和基本作用。当前提案的重点是探索 LPS 引起的低度慢性炎症对心脏线粒体质量的影响，以及这种影响在衰老心脏中如何变化。我们认为，有害脂质介质的产生增加在调节线粒体质量从而导致老年心脏表型方面发挥着关键作用。拟议的研究将（1）确定长期暴露于低剂量 LPS 的年轻和老年小鼠的类二十烷酸谱、线粒体质量和心脏功能的时间过程和特征； (2)评价生物活性脂质介质在调节线粒体质量中的作用； (3)探讨衰老过程中无菌环境对心脏功能和线粒体的影响。无菌（无菌）小鼠和无菌环境将用于剖析宿主和 LPS 之间的相互作用。这种方法将使我们能够探索环境毒素如何影响类二十烷酸谱和线粒体质量的基本机制，以及对从微生物群中分离的独特生物衰老过程的一些基本见解。 意义：这项工作将增加我们对内源性脂质介质的了解，并确定它们在调节年轻和老年心脏线粒体中的新作用。在研究衰老的影响时，还可以深入了解慢性低度炎症如何改变类二十烷酸的分布并影响线粒体。