Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries. MicroRNAs (miRNAs) are endogenous, small, non-coding RNAs that downregulate the expression of specific proteins. Several miRNAs are dysregulated in PCOS women, and a few have been implicated in PCOS metabolic manifestations. MicroRNA-21 (miR-21) is an attractive target because it is one of the most upregulated circulating miRNAs in PCOS subjects and experimental animal models of PCOS. miR-21 is highly expressed and dynamically regulated in multiple tissues important in women and animal models of PCOS, including adipose tissue, liver and muscle that have been implicated in the metabolic dysfunction observed in PCOS. miR-21 is upregulated by androgens sine the activated androgen receptor directly binds to the miR-21 promoter. In addition, the PI3K/PTEN/Akt signaling pathway plays a central role in insulin signaling, and PTEN is a miR-21 target gene. In this proposal we will test the hypothesis that in PCOS, elevated circulating androgens, via the androgen receptor, upregulate microRNA-21 that targets and downregulates PTEN, causing upregulation of Akt activity and dysregulation of insulin intracellular signaling leading to obesity and insulin resistance. Moreover, activation of the androgen receptor increases food intake leading to obesity in PCOS which causes a positive feedback on insulin resistance?.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM121334-04
Application #
10181494
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Bernal, Federico
Project Start
Project End
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Type
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Himel, Alexandra R; Cabral, Sharon A; Shaffery, James P et al. (2018) Anxiety behavior and hypothalamic-pituitary-adrenal axis altered in a female rat model of vertical sleeve gastrectomy. PLoS One 13:e0200026
Reckelhoff, Jane F (2018) Gender differences in hypertension. Curr Opin Nephrol Hypertens 27:176-181
Torres Fernandez, Edgar D; Adams, Kristen V; Syed, Maryam et al. (2018) Long-Lasting Androgen-Induced Cardiometabolic Effects in Polycystic Ovary Syndrome. J Endocr Soc 2:949-964
Reckelhoff, Jane F; Alexander, Barbara T (2018) Reproducibility in animal models of hypertension: a difficult problem. Biol Sex Differ 9:53
Spann, Redin A; Lawson, William J; Bidwell 3rd, Gene L et al. (2018) Rodent vertical sleeve gastrectomy alters maternal immune health and fetoplacental development. Clin Sci (Lond) 132:295-312
Mahajan, Gouri J; Vallender, Eric J; Garrett, Michael R et al. (2018) Altered neuro-inflammatory gene expression in hippocampus in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 82:177-186
Cunningham Jr, Mark W; Castillo, Javier; Ibrahim, Tarek et al. (2018) AT1-AA (Angiotensin II Type 1 Receptor Agonistic Autoantibody) Blockade Prevents Preeclamptic Symptoms in Placental Ischemic Rats. Hypertension 71:886-893
Ball, Jana P; Syed, Maryam; MaraƱon, Rodrigo O et al. (2017) Role and Regulation of MicroRNAs in Aldosterone-Mediated Cardiac Injury and Dysfunction in Male Rats. Endocrinology 158:1859-1874
Dalmasso, Carolina; Patil, Chetan N; Yanes Cardozo, Licy L et al. (2017) Cardiovascular and Metabolic Consequences of Testosterone Supplements in Young and Old Male Spontaneously Hypertensive Rats: Implications for Testosterone Supplements in Men. J Am Heart Assoc 6:
Patil, Chetan N; Racusen, Lorraine C; Reckelhoff, Jane F (2017) Consequences of advanced aging on renal function in chronic hyperandrogenemic female rat model: implications for aging women with polycystic ovary syndrome. Physiol Rep 5:

Showing the most recent 10 out of 11 publications