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

概述：衰老是一个自然的过程，涉及生物系统的进行性衰退，如线粒体的结构和功能。许多外源性因素在一生中都会影响线粒体的质量，包括暴露在环境毒素中，如脂多糖(LPS)。据预测，随着年龄的增长，线粒体损伤的易感性增加。然而，慢性应激源对线粒体质量的影响以及随后衰老的影响尚不清楚。我的研究兴趣在于研究心脏内的长链n-3和n-6多不饱和脂肪酸(PUFA)。这些脂肪酸是磷脂膜的必需成分，也是二十烷类化合物大家族的前体。N-3和n-6多不饱和脂肪酸的代谢通过环氧合酶(COX)、脂氧合酶(LOX)和细胞色素P450(CYP)三个主要酶系统产生大量具有生物活性的二十烷基类化合物。许多二十烷基类化合物是在炎症反应中产生的；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了解。我们的初步数据表明，内毒素可增加亚油酸代谢产物的生成，从而降低线粒体质量。*目的：我的NSERC计划的目标是发现心脏内源性产生的生物活性脂质介质的新的和基本的作用。目前这项提议的重点是探讨由内毒素引起的低级别慢性炎症对心脏线粒体质量的影响，以及这种影响在老年心脏中是如何变化的。我们认为，有害脂质介质的增加在调节线粒体质量方面发挥了关键作用，这有助于老年心脏表型的形成。这项拟议的研究将(1)建立长期低剂量内毒素暴露的年轻和老年小鼠的二十烷基类化合物、线粒体质量和心脏功能的时间进程和特征；(2)评估生物活性脂质介质在调节线粒体质量方面的作用；以及(3)探索无菌环境对衰老过程中心脏功能和线粒体的影响。无菌(无菌)小鼠和无菌环境将被用来剖析宿主和内毒素之间的相互作用。这种方法将使我们能够探索环境毒素如何影响二十烷基类化合物和线粒体质量的基本机制，以及从微生物群中分离出来的独特的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方面的新角色。也为了解慢性低度炎症将如何改变二十烷基类化合物的轮廓和影响线粒体，同时研究衰老的影响提供了洞察力。**

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. **