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: 7273894
• 负责人: PAUL WENTWORTH
• 金额: $ 18.5万
• 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/7273894
• 关键词: Affect; Age; Aging; Aldehydes; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anatomic Sites; Animals; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Biological; Blood Vessels; Cells; Chemicals; Chronic; Disease; Distant; Elderly; Exposure to; Half-Life; Human; In Vitro; Inflammation; Inflammatory; Life; Link; Liquid substance; Location; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediator of activation protein; Modeling; Mouse Strains; Mus; Organ; Peptides; Physiological; Plasma; Research; Research Personnel; Severities; System; Tissues; Transgenic Organisms; Vascular Endothelium; age effect; age related; body system; brain tissue; in vivo; leukocyte activation; mouse model; neurotoxic; peptide A; programs; response

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).

描述（由申请人提供）：该提案是针对RFA-AG-05-011提交的，探讨了新发现的与年龄相关的炎症脂质醛，依Heronal-A和-b的变化。我们最近表明，在人动脉粥样硬化斑块材料，等离子体和脑组织中，动脉粥样硬化存在于体内。至关重要的是，我们已经表明，在白细胞激活时，发炎动脉内的动脉动脉的水平显着升高。此外，我们已经在体外表明，牵引力具有生物学作用，使它们成为炎症介质。此外，我们已经表明，触式促进了神经毒性β-淀粉样蛋白（A？）肽的错误折叠和聚集。动脉龙在几分钟的小鼠中具有血浆半衰期，在细胞和流体室之间可以自由扩散，因此可以影响远距离的解剖部位远离炎症的活跃位置。因此，作为表征血管内皮中动脉粥样硬化的慢性炎症的副产品，动脉粥样硬化可以用作后期生命疾病的拮抗化学介质，均可作为动脉粥样硬化进展和阿尔茨海默氏病（AD）。因此，我们假设动脉粥样硬化介质可能是一种化学联系，可以解释已知的流行病学收敛和AD之间的流行病学收敛，两种主要的衰老疾病，也可以作为一个器官中衰老的一个例子，可以影响另一个器官的衰老。 。该R21提案概述了动物系统中的研究，以量化衰老对动脉水平的影响，以及早期生活中的动脉疫苗暴露是否会影响以后的生命病理生理变化。该提案将通过研究以下三个特定目的来研究与生理和病理生理衰老变化与生理和病理生理衰老变化的关系： 1）具体目的＃1确定年龄和动脉粥样硬化进展对两种鼠模型的动脉粥样硬化模型，Apo-E缺乏症（APOE-/ - ）和LDLRECEPTOR缺陷（LDL - / - ）的年龄和血管组织水平的影响小鼠菌株。 2）具体目的＃2确定年龄和动脉粥样硬化进展对动脉粥样硬化的ApoE - / - 和LDL - / - 鼠模型中动脉粥样硬化中脑组织水平的影响。 3）具体目的＃3确定在动脉粥样硬化模型中，早年暴露于动脉粥样硬化的疾病和阿尔茨海默氏病的晚期衰老疾病的严重程度是否增加模型（杰克逊实验室）。

项目成果

Cholesterol secosterol adduction inhibits the misfolding of a mutant prion protein fragment that induces neurodegeneration.

胆固醇仲甾醇加合可抑制引起神经变性的突变朊病毒蛋白片段的错误折叠。

• DOI: 10.1002/anie.200904524
• 发表时间: 2009
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Scheinost,JohannaC;Witter,DanielP;Boldt,GrantE;Offer,John;WentworthJr,Paul
• 通讯作者: WentworthJr,Paul

The ratio of cholesterol 5,6-secosterols formed from ozone and singlet oxygen offers insight into the oxidation of cholesterol in vivo.

由臭氧和单线态氧形成的胆固醇 5,6-仲甾醇的比例可以深入了解体内胆固醇的氧化。

• DOI: 10.1039/b821584g
• 发表时间: 2009
• 期刊: Chemical communications (Cambridge, England)
• 作者: Wentworth,AnitaD;Song,Byeong-Doo;Nieva,Jorge;Shafton,Asher;Tripurenani,Sangeetha;WentworthJr,Paul
• 通讯作者: WentworthJr,Paul