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

描述（由申请人提供）：我计划在一种新的灵长类动物衰老模型中研究热休克蛋白（HSP）70和90与代谢疾病负荷之间的关系。这些伴侣蛋白，特别是HSP 70，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组的HSP 70和90的循环和组织水平，并将其与血糖和血管健康参数联系起来。然后在年龄多样化队列中纵向评价这些表征个体应激反应的终点（H10人类年当量），以便更充分地了解年龄相关合并症的自然史。在研究新的干预措施之前，这种理解是必要的，正如在本培训期的后期提出的那样。我将选择低HSP 70的灵长类动物进行研究，使用已知增加HSP 70的药理学试剂来证实这种伴侣蛋白在介导年龄相关疾病发展风险中所起的假设作用。我的近期目标是建立伴侣蛋白，应激反应和猴子代谢疾病指数之间的关系，并在此背景下，使人们能够了解血糖控制下降和血管功能障碍的个体风险。糖尿病相关疾病在葡萄糖暴露程度方面具有共同基础，因此血糖控制指标是中心焦点。这种对衰老和疾病的综合评价是建立新的衰老大动物模型和新的生物学机制的重要转化步骤。猴群表现出自发性肥胖和糖尿病，并食用西方饮食，这增强了本研究对HSP 70在衰老生物学中作用的转化相关性。我的长期职业目标包括通过与人类健康相关的独立研究，并涉及决定个人HSP特征及其导致的年龄相关疾病发展轨迹的因素之间的相互作用，从而最佳地利用这一群体资源。研究环境非常适合我的需求，可以接触到猴子，还有一个全面的导师团队，为我提供衰老、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：该项目的相关性是基于对适当动物模型的未满足需求，在该模型中了解年龄相关的胰岛素抵抗和血管功能障碍的演变，并提出这些变化的机制基础。这项工作的重要性在于它的转化性质和对老年人的科学研究和治疗模式的直接影响，这些老年人有患上胰岛素抵抗、血管疾病及其后遗症等并发症的风险。

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.