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

年龄相关代谢疾病灵长类动物模型中的伴侣蛋白

基本信息

批准号：
8129663
负责人：
Kylie Kavanagh
金额：
$ 11.54万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8129663
关键词：
Accounting Address Affect Age Aging Animal Model Animals Biological Biological Markers Biology of Aging Biometry Blood Blood Pressure Blood Vessels Body Composition Breeding Cells Cercopithecus tantalus Cholesterol Comorbidity Data Deterioration Development Diabetes Mellitus Diet Disease Drug Prescriptions Environment Evaluation Evolution Fasting Fatty acid glycerol esters Foundations Fructosamine Functional disorder Genetic Transcription Genome Mappings Glucose Glycosylated Hemoglobin Glycosylated hemoglobin A Goals Health Heat Stress Disorders Heat shock proteins Heat-Shock Proteins 70 Heat-Shock Proteins 90 Heat-Shock Response High Density Lipoprotein Cholesterol Homeostasis Human Hyperglycemia Hypertriglyceridemia Individual Insulin Insulin Resistance Intervention Investigation Life Lipids Literature Longevity Maintenance Measures Mediating Mediator of activation protein Mentors Metabolic Metabolic Diseases Modeling Molecular Chaperones Monkeys Mononuclear Muscle National Center for Research Resources Natural History Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Parents Pathogenesis Peripheral Phenotype Physiologic pulse Physiological Physiology Placebos Plasma Play Population Positioning Attribute Primates Proteins Randomized Controlled Trials Relaxation Reporting Research Research Design Research Methodology Resources Risk Risk Factors Role Sampling Staging Stress Testing Time Tissues Training Vascular Diseases Vascular resistance Work age group age related aged arterial stiffness atherogenesis base biological adaptation to stress burden of illness cardiovascular risk factor career cohort disorder risk fasting glucose genetic pedigree geranylgeranylacetone glucose metabolism glycation glycemic control heat-shock factor 1 improved indexing insulin sensitivity intravenous glucose tolerance test novel preclinical study protein expression protein profiling public health relevance research study response sex transcription factor treatment effect vervet waist circumference

项目摘要

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.

描述（由申请人提供）：我计划在一种新颖的衰老模型中研究热休克蛋白（HSP）70和90与代谢疾病负担之间的关系。这些伴侣蛋白，尤其是HSP70随着衰老而降低，被视为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HSP70和90的循环和组织水平，并将其与血糖和血管健康参数相关联。这些终点具有对压力反应的表征，然后将在年龄多样性的队列中纵向评估（H10人类年），以使与年龄相关的核心的自然历史将得到更充分的了解。如本培训期的后期，在研究新干预措施之前是必需的。我将使用已知增加HSP70的药理学剂来选择低HSP70的灵长类动物进行研究，以证实该伴侣在介导与年龄相关疾病发展风险中所起的假设作用。我的直接目标是建立伴侣蛋白，猴子中的胁迫反应和代谢疾病指标之间的关系，并能够理解在这种情况下血糖控制下降和血管功能障碍下降的个人风险。与年龄相关的疾病在葡萄糖暴露程度上具有共同的基础，因此血糖控制的指标是核心焦点。对衰老和疾病的全面评估是建立新的大型衰老模型和一种新的生物学机制的重要转化步骤。猴子殖民地表现出自发的肥胖症和糖尿病，并消耗西方饮食，从而增强了这项研究对HSP70在衰老生物学中的作用的转化相关性。我的长期职业目标是通过与人类健康相关的独立研究来最佳地利用这一菌落资源，并涉及确定个人HSP概况的因素之间的相互作用及其对年龄相关疾病发展的轨迹。通过提供对猴子和全面的导师团队的访问，该研究环境非常适合我的需求，该团队将为我提供衰老，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：该项目的相关性基础是对适当的动物模型的未满足，以了解与年龄相关的胰岛素抵抗和血管功能障碍的发展，并为这些变化提出了机械基础。这项工作的重要性在于其转化性质以及对衰老个体的科学研究和治疗范式的直接影响，用于发展胰岛素抵抗，血管疾病及其序列的合并症。