Investigating the link between the atheronals and aging

描述（由申请人提供）：本提案应RFA-AG-05-011提交，探讨了新发现的炎症衍生的脂质醛，动脉粥样硬化- a和-B的年龄相关变化。我们最近的研究表明，动脉粥样硬化物质、血浆和脑组织中存在体内动脉粥样硬化斑块。关键的是，我们已经表明，炎症动脉内的动脉粥样硬化水平在白细胞激活时显着升高。此外，我们已经在体外证明，动脉粥样硬化具有生物效应，使其成为炎症介质。此外，我们已经证明动脉粥样硬化加速了神经毒性β -淀粉样蛋白（A?）肽的错误折叠和聚集。动脉粥样硬化在小鼠体内的血浆半衰期为几分钟，可在细胞和液体间自由扩散，因此可影响远离炎症活跃部位的远处解剖部位。因此，作为血管内皮内动脉粥样硬化的慢性炎症的副产物，动脉粥样硬化可能是晚年疾病的拮抗化学介质，包括动脉粥样硬化进展和阿尔茨海默病（AD）。因此，我们假设，作为炎症介质的动脉粥样硬化可能是解释动脉粥样硬化和AD（两种主要的衰老疾病）之间已知的流行病学趋同的化学联系，也可能作为一个器官系统内的衰老如何影响另一个器官系统的例子。本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，以及生命早期接触动脉粥样硬化是否会影响生命后期的病理生理变化。本研究将探讨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衰老变化的关系，研究以下三个具体目标：

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).