The research and career development activities outlined in this application have been designed to equip the candidate, Dr. Michael Stout, with the scientific and technical expertise necessary to become an independent investigator. The proposed research aims to elucidate the mechanisms responsible for the alleviation of age- related metabolic and inflammatory dysfunction by 17?-estradiol and identify the receptor(s)/pathway(s) by which these effects occur. As such, the candidate will receive additional training in signaling networks directly relevant to this area of research through intensive coursework and hands-on laboratory experience under the supervision of Drs. James Kirkland, Eduardo Chini, and Sundeep Khosla. The short-term objectives of this application are to enhance the candidate's knowledge of nutrient-sensing and inflammatory pathway interactions and develop technical skills to evaluate these relationships in culture- and animal-model systems. The long-term goals of this application are to enable the candidate, as a newly-hired faculty member, to secure protected time for research activities, establish new collaborations, and develop a novel line of research that produces competitive grant proposals for future funding. Preliminary studies performed by the candidate under the direction of Dr. James Kirkland indicate that 17?-estradiol enhances metabolic function and alleviates inflammation in older mice through pathways that are central to metabolic homeostasis and the aging process. This proposal will expand upon these findings by unraveling the intracellular mechanisms responsible for these phenotypes while also identifying receptor(s)/pathway(s) by which 17?-estradiol elicits these downstream effects. The overall hypothesis is that 17?-estradiol signals through an uncharacterized receptor/pathway leading to activation of AMPK and alleviation of metabolic and inflammatory dysfunction. The candidate will test this hypothesis through the following aims: 1) Determine if metabolic enhancement by 17?-estradiol is AMPK-dependent; 2) Determine if 17?-estradiol reduces inflammation by suppressing mTOR and/or NFKB; and 3) Identify the receptor(s)/pathway(s) by which 17?-estradiol elicits its cellular effects. This work will significantly enhance the understanding of molecular and cellular pathways by which 17?-estradiol elicits its effects which could lead to the development of novel treatments for aging- and/or obesity-related metabolic and inflammatory disorders.

Public Health Relevance

Aging is the leading risk factor for diabetes and, like diabetes and obesity, is associated with chronic non- microbial inflammation. We found that treatment with 17?-estradiol, a nonfeminizing hormone naturally occurring in both men and women that increases maximum lifespan in mice, enhances metabolic function and alleviates inflammation in older mice through pathways that are central to metabolic function and that modulate aging. In work that could lead to development of novel treatments for age-related diabetes and inflammatory disorders, we will explore mechanisms responsible for the alleviation of age-related metabolic and inflammatory dysfunction by 17?-estradiol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Transition Award (R00)
Project #
4R00AG051661-03
Application #
9788589
Study Section
Special Emphasis Panel (NSS)
Program Officer
Fuldner, Rebecca A
Project Start
2018-09-30
Project End
2021-05-31
Budget Start
2018-09-30
Budget End
2019-05-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Nutrition
Type
Sch Allied Health Professions
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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Du, Mei; Mangold, Colleen A; Bixler, Georgina V et al. (2017) Retinal gene expression responses to aging are sexually divergent. Mol Vis 23:707-717
Gesing, Adam; Wiesenborn, Denise; Do, Andrew et al. (2017) A Long-lived Mouse Lacking Both Growth Hormone and Growth Hormone Receptor: A New Animal Model for Aging Studies. J Gerontol A Biol Sci Med Sci 72:1054-1061
Stout, Michael B; Justice, Jamie N; Nicklas, Barbara J et al. (2017) Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty. Physiology (Bethesda) 32:9-19
Stout, Michael B; Steyn, Frederik J; Jurczak, Michael J et al. (2017) 17?-Estradiol Alleviates Age-related Metabolic and Inflammatory Dysfunction in Male Mice Without Inducing Feminization. J Gerontol A Biol Sci Med Sci 72:3-15
Kirkland, James L; Stout, Michael B; Sierra, Felipe (2016) Resilience in Aging Mice. J Gerontol A Biol Sci Med Sci 71:1407-1414
Li, Rui; Steyn, Frederik J; Stout, Michael B et al. (2016) Development of a high-throughput method for real-time assessment of cellular metabolism in intact long skeletal muscle fibre bundles. J Physiol 594:7197-7213
Huffman, Derek M; Justice, Jamie N; Stout, Michael B et al. (2016) Evaluating Health Span in Preclinical Models of Aging and Disease: Guidelines, Challenges, and Opportunities for Geroscience. J Gerontol A Biol Sci Med Sci 71:1395-1406