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 sequelae.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
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National Institute on Aging Initial Review Group (NIA)
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Finkelstein, David B
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Wake Forest University Health Sciences
Schools of Medicine
United States
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Kavanagh, K; Flynn, D M; Jenkins, K A et al. (2013) Stearidonic and ýý-linolenic acids in echium oil improves glucose disposal in insulin resistant monkeys. Prostaglandins Leukot Essent Fatty Acids 89:39-45
Kavanagh, Kylie; Wylie, Ashley T; Tucker, Kelly L et al. (2013) Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates. Am J Clin Nutr 98:349-57
Kavanagh, Kylie; Espeland, Mark A; Sutton-Tyrrell, Kim et al. (2013) Liver fat and SHBG affect insulin resistance in midlife women: the Study of Women's Health Across the Nation (SWAN). Obesity (Silver Spring) 21:1031-8
Kavanagh, Kylie; Flynn, David M; Jenkins, Kurt A et al. (2011) Restoring HSP70 deficiencies improves glucose tolerance in diabetic monkeys. Am J Physiol Endocrinol Metab 300:E894-901
Saisho, Yoshifumi; Manesso, Erica; Butler, Alexandra E et al. (2011) Ongoing beta-cell turnover in adult nonhuman primates is not adaptively increased in streptozotocin-induced diabetes. Diabetes 60:848-56
Kavanagh, K; Dozier, B L; Chavanne, T J et al. (2011) Fetal and maternal factors associated with infant mortality in vervet monkeys. J Med Primatol 40:27-36
Rowe, Patrick A; Kavanagh, Kylie; Zhang, Li et al. (2011) Short-term hyperglycemia increases arterial superoxide production and iron dysregulation in atherosclerotic monkeys. Metabolism 60:1070-80
Kavanagh, Kylie; Flynn, David M; Nelson, Chris et al. (2011) Characterization and validation of a streptozotocin-induced diabetes model in the vervet monkey. J Pharmacol Toxicol Methods 63:296-303
Kavanagh, Kylie; Sajadian, Soraya; Jenkins, Kurt A et al. (2010) Neonatal and fetal exposure to trans-fatty acids retards early growth and adiposity while adversely affecting glucose in mice. Nutr Res 30:418-26