Chaperone Proteins in a Primate Model of Age-Related Metabolic Disease

项目摘要 我计划研究热休克蛋白70和90之间的关系 一种新的灵长类衰老模型中的代谢性疾病负担。这些伴侣蛋白， 尤其是HSP70，随着年龄的增长而减少，并被认为是胰岛素的重要介质 敏感性和血管功能正常。我将首先描述血液循环和组织水平 所有年龄组的HSP70和90，并将它们与血糖和血管健康相关 参数。这些具有个体应激反应特征的端点将是 在不同年龄的队列中进行纵向评估(相当于H10人年)，以使 与年龄相关的合并症的自然历史将得到更充分的理解。这种理解是 学习新干预措施之前的必备条件，如本培训后几年所建议 句号。我将选择HSP70低的灵长类动物进行研究，使用一种已知的 增加HSP70以证实该伴侣蛋白在中介中发挥的假设作用 与年龄相关的疾病发展的风险。我的近期目标是建立一种关系 在伴侣蛋白、应激反应和猴子代谢性疾病指标之间， 并使了解个体血糖控制和血管功能下降的风险 在这种情况下的功能障碍。与年龄相关的疾病在血糖程度上有一个共同的基础 暴露和血糖控制指数是中心关注点。这项综合评估 衰老和疾病是建立新的大型动物模型的重要转换步骤 衰老和一种新的生物机制。猴群表现出自发性肥胖和 糖尿病和西方饮食，这增强了这个词的翻译相关性 热休克蛋白70的S在衰老生物学中的作用研究我的长期职业目标包括成为 处于最佳地位，通过独立研究利用这一群体资源，即 与人类健康有关，涉及决定个人健康的因素之间的相互作用 与年龄相关的疾病发展的热休克蛋白图谱及其结果轨迹。这项研究 环境是唯一适合我的需求的，因为它提供了对猴子的访问和 全面的导师团队，将为我提供老龄化、生物统计学和 血管健康。

Project Summary I plan to study the relationship between heat shock proteins (HSP) 70 and 90 with metabolic disease burden in a novel primate model of aging. These chaperone proteins, particularly HSP70, decrease with aging and are implicated as important mediators of insulin sensitivity and normal vascular function. I will first characterize circulating and tissue levels of HSP70 and 90 across all age groups and relate them to glycemic and vascular health parameters. These endpoints with characterization of individual responses to stress will then be evaluated longitudinally (H10 human years equivalent) in an age-diverse cohort such that the natural history of age-related co-morbidities will be more fully understood. This understanding is requisite prior to studying novel interventions, as proposed in the later years of this training period. I will select primates with low HSP70 for study using a pharmacological agent known to increase HSP70 to substantiate the hypothesized role that this chaperone plays in mediating risk for age-related disease development. My immediate goals are to establish a relationship between chaperone proteins, the stress response, and indices of metabolic disease in monkeys, and enable understanding of individual risk of declining glycemic control and vascular dysfunction in this context. Age-related diseases have a common basis in the degree of glucose exposure and thus indices of glycemic control are central focus. This comprehensive evaluation of aging and disease are important translational steps in establishing a new large animal model of aging and a new biological mechanism. The monkey colony shows spontaneous obesity and diabetes and consumes a western diet which enhances the translational relevance of this research into HSP70's role in aging biology. My long-term career goals involve becoming optimally positioned to take advantage of this colony resource by independent research that is relevant to human health and involves interplay between factors that determine an individual's HSP profile and their resultant trajectory for age-related disease development. The research environment is uniquely suited to my needs by providing access to the monkeys and a comprehensive mentor team that will provide me new expertise in aging, biostatistics, and vascular health.