The hypothesis underlying this research project is that genetic variants or a stable metabolic imprint lead to abnormal function in cells from multiple tissues in PCOS; and that the molecular fingerprint of the genetic variation/stable imprint can be identified by comparative analysis of gene and protein expression profiles. Further, we postulate that similarities in the molecular fingerprints of cells from different tissues will establish the network of genes whose expression is altered in PCOS, and ultimately, the proximate cause for the PCOS molecular phenotype. A second hypothesis is that the molecular phenotype of PCOS can be induced as well as reversed by pharmacological manipulation of cell signaling pathways. By understanding the mechanisms of PCOS mimicry and pharmacological correction we hope to gain insight into signaling pathways that are affected in PCOS. An important dividend of the analysis of differential gene and protein expression will be the identification of new candidate genes that can be tested for association and linkage to PCOS in family -- based studies in Project II. The experiments on the pharmacologic induction/reversal of a PCOS phenocopy may disclose novel therapeutic strategies.
Specific Aim 1 is to identify differentially expressed genes and proteins in PCOS by comparing normal cells and cells collected from women with PCOS.
Specific Aim 2 is to determine whether the molecular phenotype of PCOS cells in long-term culture is consistent with in vivo patterns of gene and protein expression; and whether the differential patterns of gene expression are the result of altered gene transcription.
Specific Aim 3 is to test models based on initial results from expression profiling indicating that PCOS cells from different tissues display an altered pattern of gene expression and protein expression in long term culture.
Specific Aim 4 is to characterize the effect of valproic acid on steroidogenesis and gene and protein expression in theca and granulosa cells, and gene and protein expression in skeletal muscle cells, adipocytes, fibroblasts and endometrial cells.
| Gorsic, Lidija K; Kosova, Gulum; Werstein, Brian et al. (2017) Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 102:2862-2872 |
| Legro, Richard S; Kunselman, Allen R; Stetter, Christy M et al. (2017) Normal Pubertal Development in Daughters of Women With PCOS: A Controlled Study. J Clin Endocrinol Metab 102:122-131 |
| Ketefian, Aline; Jones, Michelle R; Krauss, Ronald M et al. (2016) Association study of androgen signaling pathway genes in polycystic ovary syndrome. Fertil Steril 105:467-73.e4 |
| Tee, Meng Kian; Speek, Mart; Legeza, Balázs et al. (2016) Alternative splicing of DENND1A, a PCOS candidate gene, generates variant 2. Mol Cell Endocrinol 434:25-35 |
| Dumesic, Daniel A; Oberfield, Sharon E; Stener-Victorin, Elisabet et al. (2015) Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr Rev 36:487-525 |
| Hayes, M Geoffrey; Urbanek, Margrit; Ehrmann, David A et al. (2015) Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 6:7502 |
| Brower, Meredith A; Jones, Michelle R; Rotter, Jerome I et al. (2015) Further investigation in europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of Chinese individuals. J Clin Endocrinol Metab 100:E182-6 |
| Du, Ping; Camacho, Fabian; McCall-Hosenfeld, Jennifer et al. (2015) Human Papillomavirus Vaccination Among Adults and Children in 5 US States. J Public Health Manag Pract 21:573-83 |
| Feiner, John R; Gropper, Michael A; Toy, Pearl et al. (2015) A Clinical Trial to Detect Subclinical Transfusion-induced Lung Injury during Surgery. Anesthesiology 123:126-35 |
| McAllister, Jan M; Legro, Richard S; Modi, Bhavi P et al. (2015) Functional genomics of PCOS: from GWAS to molecular mechanisms. Trends Endocrinol Metab 26:118-24 |
Showing the most recent 10 out of 153 publications
