Investigating the link between the atheronals and aging

描述（由申请人提供）：本提案是为响应RFA-AG-05-011而提交的，旨在探索新发现的炎症源性雌二醇（atheronal-A和B）的年龄相关变化。我们最近发现动脉粥样硬化存在于人体动脉粥样硬化斑块物质、血浆和脑组织中。重要的是，我们已经表明，炎症动脉内的动脉粥样硬化水平在白细胞活化后显著升高。此外，我们已经在体外证明动脉粥样硬化具有生物学效应，使其成为炎症介质。此外，我们已经表明，动脉粥样硬化加速错误折叠和聚集的神经毒性β-淀粉样蛋白（A？）肽。动脉粥样硬化剂在小鼠中的血浆半衰期为几分钟，可在细胞和流体隔室之间自由扩散，因此可影响远离炎症活动部位的远距离解剖部位。因此，作为表征血管内皮内的动脉粥样硬化的慢性炎症的副产物，动脉粥样硬化剂可以充当晚年疾病（动脉粥样硬化进展和阿尔茨海默病（AD））的拮抗性化学介质。因此，我们假设动脉粥样硬化，作为炎症介质，可能是一种化学联系，解释了动脉粥样硬化和AD，两种主要的衰老疾病之间的流行病学收敛，也可以作为一个例子，一个器官系统内的衰老如何影响另一个。这一R21提案概述了动物系统的研究，以量化衰老对动脉粥样硬化水平的影响，以及早期生命中的动脉粥样硬化暴露是否会影响晚年的病理生理变化。本提案将通过调查以下三个具体目标，调查动脉粥样硬化水平的年龄相关变化与器官功能的生理和病理生理老化变化之间的关系： 1)具体目标#1确定年龄和动脉粥样硬化进展对两种动脉粥样硬化小鼠模型（Apo-E缺陷（ApoE-/-）和LDL受体缺陷（LDL-/-）小鼠品系）中动脉粥样硬化的血浆和血管组织水平的影响。2)具体目标#2确定年龄和动脉粥样硬化进展对ApoE-/-和LDL-/-动脉粥样硬化小鼠模型中动脉粥样硬化脑组织水平的影响。3)具体目标#3在动脉粥样硬化的鼠模型、ApoE-/-和LDL-/-以及人APP转基因小鼠模型（杰克逊实验室）中确定早期暴露于动脉粥样硬化是否导致动脉粥样硬化和阿尔茨海默病的晚年衰老障碍的严重程度增加。

DESCRIPTION (provided by applicant): This proposal, submitted in response to RFA-AG-05-011, explores the age-related changes of the newly discovered inflammation-derived lipidic aldehydes, atheronal-A and -B. We have recently shown that the atheronals are present in vivo within human atherosclerotic plaque material, plasma and brain tissue. Critically, we have shown that the levels of the atheronals within inflamed arteries are significantly elevated upon leukocyte activation. Furthermore we have shown in vitro that the atheronals have biological effects that make them inflammatory mediators. Furthermore we have shown that the atheronals accelerate the misfolding and aggregation of the neurotoxic beta-amyloid (A?) peptide. Atheronals have a plasma half-life in mice of several minutes, are freely diffusible between cells and fluid compartments and can thus can impact distant anatomic sites away from the active location of inflammation. Thus, as byproducts of the chronic inflammation that characterizes atherosclerosis within the vascular endothelium, the atheronals may serve as antagonistic chemical mediators of late life disease, both atherosclerosis progression and Alzheimer's disease (AD). We hypothesize therefore that the atheronals, as inflammatory mediators, may be a chemical link that explains the known epidemiologic convergence between atherosclerosis and AD, two major diseases of aging, and may also serve as an example of how ageing within one organ system can affect another. This R21 proposal outlines research in animal systems to quantify the effect of ageing on atheronal levels, and whether atheronal exposure in early life can impact later life pathophysiological changes. This proposal will investigate the relationships of age-related changes in atheronal levels to physiologic and pathophysiologic ageing changes in organ function by investigating the following three specific aims: 1) Specific aim #1 Determine the effect of age and atherosclerosis progression on plasma and vascular tissue levels of the atheronals in two murine models of atherosclerosis, the Apo-E deficient (ApoE-/-) and LDLreceptor deficient (LDL-/-) mouse strains. 2) Specific aim #2 Determine the effect of age and atherosclerosis progression on brain tissue levels of the atheronals in the , ApoE-/- and LDL-/- murine models of atherosclerosis. 3) Specific aim # 3 Determine if early age exposure to atheronals results in an increased severity of the late life ageing disorders of atherosclerosis and Alzheimer's disease in murine models of atherosclerosis, ApoE-/- and LDL-/- and a human APP transgenic mouse model (Jackson labs).