Investigating the link between the atheronals and aging

研究动脉粥样硬化与衰老之间的联系

• 批准号: 7124089
• 负责人: PAUL WENTWORTH
• 金额: $ 22.87万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7124089
• 关键词: Alzheimer' s disease; aging; aldehydes; amyloid proteins; atherosclerosis; blood chemistry; blood vessels; brain; early experience; genetically modified animals; inflammation; laboratory mouse; lipid transport; lipids; pathologic process

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 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).

描述（由申请人提供）：该提案是针对 RFA-AG-05-011 提交的，探讨了新发现的炎症衍生的脂质醛、atheronal-A 和 -B 与年龄相关的变化。我们最近表明，动脉粥样硬化斑块存在于体内人类动脉粥样硬化斑块材料、血浆和脑组织中。重要的是，我们已经证明，白细胞激活后，发炎动脉内的动脉粥样硬化水平显着升高。此外，我们在体外证明动脉粥样硬化斑块具有使其成为炎症介质的生物效应。此外，我们还发现动脉粥样硬化加速了神经毒性β-淀粉样肽的错误折叠和聚集。动脉粥样硬化斑块在小鼠体内的血浆半衰期为几分钟，可在细胞和液体室之间自由扩散，因此可以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特征的慢性炎症的副产物，动脉粥样硬化可能充当晚年疾病（动脉粥样硬化进展和阿尔茨海默氏病（AD））的拮抗化学介质。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，可以解释动脉粥样硬化和阿尔茨海默氏症（两种主要的衰老疾病）之间已知的流行病学趋同性，并且也可以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。 。该 R21 提案概述了动物系统研究，以量化衰老对动脉粥样硬化斑块水平的影响，以及生命早期暴露于动脉粥样硬化斑块是否会影响晚年的病理生理变化。该提案将通过研究以下三个具体目标来研究动脉粥样硬化斑块水平与年龄相关的变化与器官功能的生理和病理生理老化变化的关系： 1) 具体目标#1 确定年龄和动脉粥样硬化进展对两种小鼠动脉粥样硬化模型（Apo-E 缺陷型 (ApoE-/-) 和 LDL 受体缺陷型 (LDL-/-)）中血浆和血管组织动脉粥样硬化水平的影响小鼠品系。 2) 具体目标#2 确定年龄和动脉粥样硬化进展对动脉粥样硬化小鼠模型、ApoE-/- 和 LDL-/- 动脉粥样硬化脑组织水平的影响。 3) 具体目标#3 确定在动脉粥样硬化、ApoE-/- 和 LDL-/- 小鼠模型以及人类 APP 转基因小鼠中，幼年暴露于动脉粥样硬化斑块是否会导致晚年动脉粥样硬化和阿尔茨海默氏病的严重程度增加模型（杰克逊实验室）。