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

描述(申请人提供)：我计划在一个新的灵长类动物衰老模型中研究热休克蛋白(HSP)70和90与代谢性疾病负担的关系。这些伴侣蛋白，尤其是HSP70，随着年龄的增长而减少，并被认为是胰岛素敏感性和正常血管功能的重要介质。我将首先描述所有年龄段的循环和组织中HSP70和90的水平，并将它们与血糖和血管健康参数联系起来。这些具有个体应激反应特征的终点将在不同年龄的队列中进行纵向评估(相当于人类10年)，以便更充分地了解与年龄相关的共病的自然历史。在学习新的干预措施之前，这一理解是必要的，如本培训期间的后几年所建议的。我将选择HSP70低的灵长类动物进行研究，使用一种已知能增加HSP70的药理学试剂来证实这种伴侣蛋白在调节与年龄相关的疾病发展风险方面所起的假设作用。我的近期目标是建立伴侣蛋白、应激反应和猴子代谢性疾病指标之间的关系，并在此背景下了解个体血糖控制下降和血管功能障碍的风险。与年龄相关的疾病在葡萄糖暴露程度上有一个共同的基础，因此血糖控制指数是中心焦点。这种对衰老和疾病的综合评估是建立新的大动物衰老模型和新的生物学机制的重要翻译步骤。猴群表现出自发性肥胖和糖尿病，并食用西方饮食，这增强了这项研究对热休克蛋白70在衰老生物学中的S作用的翻译相关性。我的长期职业目标包括通过与人类健康相关的独立研究，成为利用这一群体资源的最佳位置，并涉及决定个人HSP特征的因素与其由此导致的与年龄相关的疾病发展轨迹之间的相互作用。研究环境特别适合我的需求，因为它提供了接触猴子的途径，以及一个全面的导师团队，将为我提供老龄化、生物统计学和血管健康方面的新专业知识。 公共卫生相关性：该项目的相关性基础在于对适当动物模型的需求尚未得到满足，在该模型中了解与年龄相关的胰岛素抵抗和血管功能障碍的演变，并为这些变化提出机制基础。这项工作的重要性在于它的翻译性质和对老年个体的科学研究和治疗范例的直接影响，这些人有患胰岛素抵抗、血管疾病及其后遗症等共病的风险。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The relevance of the project has foundations in the unmet need for an appropriate animal model in which to understand the evolvement of age-related insulin resistance and vascular dysfunction and propose a mechanistic basis for these changes. The importance of this work is in its translational nature and immediate implications for scientific investigation and treatment paradigms in aging individuals at-risk for developing co-morbidities such as insulin resistance, vascular disease and their sequalae.