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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=687826
• 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：衰老是涉及生物系统（如线粒体结构和功能）逐渐衰退的自然过程。一生中许多外源性因素会影响线粒体质量，包括暴露于环境毒素，如脂多糖（LPS）。据预测，随着年龄的增长，线粒体损伤的易感性会增加。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的必需成分，是一大家族类二十烷的前体。n-3和n-6 PUFA的代谢通过三个主要的酶系统-环氧化酶（COX），脂氧化酶（LOX）和细胞色素P450 （CYP）酶产生大量的生物活性类二十烷酸。许多类二十烷酸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未知。我们的初步数据表明，脂多糖会增加cypp衍生的亚油酸代谢物的产生，从而降低线粒体质量。******目的：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。本研究的重点是探讨LPS引起的低级别慢性炎症对心肌线粒体质量的影响，以及这种影响在老年心脏中的变化。我们提出，有害脂质介质的产生增加在调节线粒体质量中起关键作用，从而导致心脏表型老化。拟议的研究将(1)确定暴露于慢性低剂量LPS的年轻和老年小鼠的类二十烷谱、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)探讨无菌环境对衰老过程中心功能和线粒体的影响。无菌小鼠和无菌环境将被用来解剖宿主和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概况和线粒体质量的基本机制，以及从微生物群中分离出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认识，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，也为理解慢性低度炎症如何改变类二十烷酸谱和影响线粒体提供了见解。**