The NU SCOR explores the overarching hypothesis that genetic variation resulting in hyperandrogenemia produces the phenotypic features of the polycystic ovary syndrome (PCOS) by androgen programming in utero as well as by ongoing androgen actions at critical developmental periods and in the adult. We have found sex-specific metabolic phenotypes in PCOS families, mapped several PCOS susceptibility genes, developed animal models of androgen programming and discovered that androgen-mediated estrogen resistance is an important mechanism for these androgen actions. It is clear that the genes for PCOS so far identified do not explain the high heritability of this disorder. We will investigate te mechanisms for this deficit in heritability as well as the molecular mechanisms by which estrogen resistance can produce obesity and metabolic abnormalities in PCOS. Our strategy for achieving the SCOR objectives is to directly investigate the genetic, epigenetic and hormonal determinants PCOS in three highly interactive, synergistic and interdisciplinary projects: Projects I and II are clinical research projects and Projects III will utilize a novel non-human primate model. Although each project is discrete, the proposed SCOR as a whole will continue to comprehensively investigate novel mechanisms for the pathogenesis of PCOS. Project I will test the hypothesis that rare genetic variants will account for much of the deficit in heritabilityof PCOS. We predict that we will identify rare variants in pathways implicated in the pathogenesis of PCOS in mapping of common variants, such as TGF? signaling, Wnt signaling, insulin signaling, gonadotropin action and extracellular matrix, as well as rare variants in genes in novel pathways. Project II will test the hypothesis that a significant component of the heritability of PCOS is due to epigenetic changes including variation in methylation patterns, that these changes in methylation patterns correlate with changes in expression patterns, and that these changes in methylation are due to either specific changes in the DNA or environmental factors including the in utero environment. Project III will develop a novel non-human primate (marmoset) model of diet-induced obesity to test the hypothesis that androgenic programming of metabolic features of PCOS is mediated by induction of resistance to the actions of estradiol in target hypothalamic neurons that modulate energy homeostasis. These studies are extremely innovative, highly synergistic and likely to have a major impact on the field through elucidating the pathogenesis of PCOS and its metabolic phenotypes.

Public Health Relevance

PCOS is one of the most common endocrine disorders of reproductive age women, affecting approximately 7% of this population. It is a leading risk factor for metabolic syndrome and type 2 diabetes mellitus in adolescent as well as adult women. The NU SCOR will elucidate the causes of PCOS leading to new prevention and treatment strategies. A novel non-human primate model of obesity will be developed that will be very important for studies of the causes of this epidemic disorder.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
5P50HD044405-12
Application #
8549283
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q (50))
Program Officer
Eisenberg, Esther
Project Start
2002-09-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2013
Total Cost
$1,051,976
Indirect Cost
$249,928
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Torchen, Laura C; Fogel, Naomi R; Brickman, Wendy J et al. (2014) Persistent apparent pancreatic ?-cell defects in premenarchal PCOS relatives. J Clin Endocrinol Metab 99:3855-62
Liu, D M; Torchen, L C; Sung, Y et al. (2014) Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome. Hum Reprod 29:2764-72
Bernal-Mizrachi, Ernesto; Kulkarni, Rohit N; Scott, Donald K et al. (2014) Human ?-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map. Diabetes 63:819-31
Raja-Khan, Nazia; Urbanek, Margrit; Rodgers, Raymond J et al. (2014) The role of TGF-* in polycystic ovary syndrome. Reprod Sci 21:20-31
Bhatt, Surabhi; Mutharasan, Priscilla; Garcia, Obed A et al. (2014) The inflammatory gene pathway is not a major contributor to polycystic ovary snydrome. J Clin Endocrinol Metab 99:E567-71
Nicol, Lindsey E; O'Brien, Timothy D; Dumesic, Daniel A et al. (2014) Abnormal infant islet morphology precedes insulin resistance in PCOS-like monkeys. PLoS One 9:e106527
Dumesic, Daniel A; Goodarzi, Mark O; Chazenbalk, Gregorio D et al. (2014) Intrauterine environment and polycystic ovary syndrome. Semin Reprod Med 32:159-65
Nohara, Kazunari; Laque, Amanda; Allard, Camille et al. (2014) Central mechanisms of adiposity in adult female mice with androgen excess. Obesity (Silver Spring) 22:1477-84
Kobaly, Kristen; Vellanki, Priyathama; Sisk, Ryan K et al. (2014) Parent-of-origin effects on glucose homeostasis in polycystic ovary syndrome. J Clin Endocrinol Metab 99:2961-6
Liu, S; Kilic, G; Meyers, M S et al. (2013) Oestrogens improve human pancreatic islet transplantation in a mouse model of insulin deficient diabetes. Diabetologia 56:370-81

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