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

• 批准号: 8520135
• 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
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520135
• 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; research study; response; sex; transcription factor; treatment effect; vervet; waist circumference

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.

项目摘要 我计划研究热激蛋白（HSP）70和90之间的关系 新型灵长类动物衰老模型中的代谢疾病负担。这些伴侣蛋白， 特别是HSP70，随着衰老而减少，被认为是胰岛素的重要介质 灵敏度和正常的血管功能。我将首先描述循环和组织水平 HSP70和90的所有年龄段，并将其与血糖和血管健康联系起来 参数。这些终点具有对压力的各个反应的表征，然后将是 在年龄多样的同类中进行了纵向评估（H10人类年），以至于 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 在研究新干预措施之前，需要在本培训的后期提议 时期。我将使用已知的药理学剂选择低Hsp70的灵长类动物进行研究 增加HSP70以证实该伴侣在介导的假设作用 与年龄有关的疾病发展风险。我的直接目标是建立关系 在伴侣蛋白，猴子代谢疾病的压力反应和指标之间 并能够了解血糖控制和血管下降的个人风险 在这种情况下的功能障碍。与年龄有关的疾病在葡萄糖程度上具有共同的基础 暴露，因此血糖控制的指标是核心焦点。这种全面的评估 衰老和疾病是建立新的大型动物模型的重要转化步骤 衰老和一种新的生物学机制。猴子殖民地表现出自发的肥胖和 糖尿病并消耗西方饮食，从而增强了这种转化相关性 研究HSP70在衰老生物学中的作用。我的长期职业目标涉及 最佳位置可以通过独立研究来利用这一殖民资源 与人类健康有关，涉及决定个人的因素之间的相互作用 HSP概况及其与年龄相关疾病发展的轨迹。研究 通过提供对猴子和一个的访问，环境非常适合我的需求 全面的导师团队将为我提供衰老，生物统计学和 血管健康。

项目成果

Neonatal and fetal exposure to trans-fatty acids retards early growth and adiposity while adversely affecting glucose in mice.

• DOI: 10.1016/j.nutres.2010.06.006
• 发表时间: 2010-06
• 期刊: Nutrition research (New York, N.Y.)
• 作者: Kavanagh K;Sajadian S;Jenkins KA;Wilson MD;Carr JJ;Wagner JD;Rudel LL
• 通讯作者: Rudel LL

Characterization and validation of a streptozotocin-induced diabetes model in the vervet monkey.

• DOI: 10.1016/j.vascn.2011.02.003
• 发表时间: 2011-05
• 期刊: Journal of pharmacological and toxicological methods
• 影响因子: 1.9
• 作者: Kavanagh K;Flynn DM;Nelson C;Zhang L;Wagner JD
• 通讯作者: Wagner JD

Short-term hyperglycemia increases arterial superoxide production and iron dysregulation in atherosclerotic monkeys.

• DOI: 10.1016/j.metabol.2010.11.003
• 发表时间: 2011-08
• 期刊: METABOLISM-CLINICAL AND EXPERIMENTAL
• 影响因子: 9.8
• 作者: Rowe, Patrick A.;Kavanagh, Kylie;Zhang, Li;Harwood, H. James, Jr.;Wagner, Janice D.
• 通讯作者: Wagner, Janice D.