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.
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.
|Steyn, Frederik J; Ngo, Shyuan T; Chen, Vicky Ping et al. (2018) 17?-estradiol acts through hypothalamic pro-opiomelanocortin expressing neurons to reduce feeding behavior. Aging Cell 17:|
|Masser, Dustin R; Hadad, Niran; Porter, Hunter et al. (2018) Analysis of DNA modifications in aging research. Geroscience 40:11-29|
|Reagan, Alaina M; Gu, Xiaowu; Paudel, Sijalu et al. (2018) Age-related focal loss of contractile vascular smooth muscle cells in retinal arterioles is accelerated by caveolin-1 deficiency. Neurobiol Aging 71:1-12|
|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|
|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|
|Chen, Vicky Ping; Gao, Yang; Geng, Liyi et al. (2016) Butyrylcholinesterase Deficiency Promotes Adipose Tissue Growth and Hepatic Lipid Accumulation in Male Mice on High-Fat Diet. Endocrinology 157:3086-95|
|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|
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