Carlos Oscar Stocco
University Of Illinois At Chicago
Project start date: 2011-01-01
Project end date: 2012-12-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Carlos Oscar Stocco
MOLECULAR PATHWAYS CONTROLLING OVARIAN GENE EXPRESSION
Carlos Oscar Stocco, Phd
University Of Illinois At Chicago, 310 Aob, M/c 672, Chicago, Il 60612
Grant 5R01HD057110-03 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Coordinated activation and repression of genes are essential for the normal progress of the ovarian cycle. Ovarian granulosa cells express high levels of the transcription factors GATA-4 and GATA-6. In cell cultures, these transcription factors were shown to play key roles in the expression of enzymes involved in steroidogenesis. We have demonstrated in several recently published papers that GATA-4 is critical for the production of estradiol, which is essential for granulosa cell proliferation and follicle maturation. In addition, the finding that low expression of GATA-4 is associated with follicular cell death suggests that this factor also plays a survival role in the ovary. Because GATA-4 and GATA-6 null mice are embryonic lethal, the ultimate role of GATA in ovarian function remains unknown. This study is therefore designed to determine the physiological role of GATA-4 and GATA-6 in ovarian steroidogenesis, follicular development, and female fertility. The specific aims of this study are 1- To generate ovarian-specific GATA-4 and GATA-6 null mice in order to find out the explicit roles of these transcription factors in the ovary in vivo. The Cre-lox technology will be used to delete part of the coding region of GATA-4, GATA-6, or their combination. We expect these mice to have severe defects in steroid production and in follicular development. 2- To determine the effect of GATA-4 and GATA-6 deletion on ovarian cells in vitro. Granulosa cells lacking GATA-4, GATA-6, or both will be used to examine the specific roles of these factors in steroidogenesis, cell proliferation, granulosa-cell hormone response, and gene expression. 3- To identify those genes that are regulated by GATA-4 and GATA-6 in fully functional ovaries in vivo, we will use ChIP-on-chip assays. All the results obtained to date indicate that GATA-4 and GATA-6 may play a crucial role in the normal function of the ovary. We expect from this investigation to clearly define the function of GATA-4 and GATA-6 in the steroidogenic capacity and growth of granulosa cells, to determine whether GATA-4 and GATA-6 have redundant effects on these cells, and to identify GATA-4 and GATA-6 target genes in the ovary. This study will not only provide critically important information on the regulatory mechanism underlying normal ovarian function but also may shed light on ovarian diseases due to improper granulosa cell function such as granulosa cell tumors and infertility. The roles of the transcription factors GATA-4 and GATA-6 in folliculogenesis and fertility will be addressed. These studies will contribute to better understanding of the cellular and molecular mechanisms that control ovarian function and improve our knowledge of the etiology of ovarian diseases such as granulosa cell tumors and infertility
Keywords: Achievement; Achievement Attainment; Activins; Address; Adenoviridae; Adenoviruses; Alleles; Allelomorphs; Androgenic Agents; Androgenic Compounds; Androgens; Androstenedione Aromatase; Animals; Apoptosis; Apoptosis Pathway; Apoptotic; Aquadiol; Aromatase; Aromatase Cytochrome P450; Assay; Bioassay; Biologic Assays; Biological Assay; CPT7; CYP 19; CYP17; CYP17A1; CYP17A1 gene; CYP19 Protein; CYPXIX; Cannot achieve a pregnancy; Causality; Cell Culture Techniques; Cell Cycle Progression; Cell Death; Cell Death, Programmed; Cell Function; Cell Growth in Number; Cell Multiplication; Cell Process; Cell Proliferation; Cell physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Cellular Proliferation; Chemotherapy-Hormones/Steroids; Code; Coding System; Cytochrome P-450 CYP19; Cytochrome P-450(AROM); Cytochrome P450 19; Cytochrome P450 19A1; Cytochrome P450, Family 19, Subfamily A, Polypeptide 1; Cytochrome P450, Subfamily XIX; Cytochrome P450, Subfamily XIX (Aromatization of Androgens); DNA; DNA Recombination; DNA recombination (naturally occurring); Defect; Deoxyribonucleic Acid; Development; Difficulty conceiving; Dimenformon; Diogyn; Diogynets; Dressing; Embryo; Embryonic; Endocrine Gland Secretion; Enzymes; Estra-1, 3, 5(10)-triene-3, 17-diol (17beta)-; Estrace; Estradiol; Estradiol-17 beta; Estradiol-17beta; Estraldine; Estrogen Synthase; Estrogen Synthetase; Estrogenic Agents; Estrogenic Compounds; Estrogens; Etiology; FSH-Releasing Protein; Fecundability; Fecundity; Female; Fertility; Gene Action Regulation; Gene Down-Regulation; Gene Expression; Gene Expression Regulation; Gene Regulation; Gene Regulation Process; Gene Targeting; Generalized Growth; Genes; Genetic Recombination; Genital System, Female, Ovary; Genomics; Granulosa Cell Neoplasm; Granulosa-Luteal Cells; Granulosa-Lutein Cells; Growth; Hormones; In Vitro; Infection; Infertility; Investigation; Knockout Mice; Knowledge; Light; Luteal Cells, Large; Mammals, Mice; Mice; Mice, Knock-out; Mice, Knockout; Microarray Analysis; Microarray-Based Analysis; Molecular; Murine; Mus; Null Mouse; Ovarian; Ovarian Cycles; Ovarian Diseases; Ovarian Disorder; Ovarian Granulosa Cell; Ovarian Interstitial Cells; Ovary; Ovocyclin; Ovocylin; P450AROM; P450C17; Paper; Pathway interactions; Photoradiation; Physiologic; Physiological; Play; Production; Progynon; Publishing; Recombination; Recombination, Genetic; Reproductive Process; Role; S17AH; Staging; Sterile coverings; Steroid Compound; Steroid biosynthesis; Steroids; Structure; Subcellular Process; Targetings, Gene; Technology; Testing; Therapeutic Androgen; Therapeutic Estradiol; Therapeutic Estrogen; Therapeutic Hormone; Tissue Growth; Transcription Repression; Transcriptional Repression; design; designing; disease causation; disease etiology; disease/disorder etiology; disorder etiology; folliculogenesis; gene repression; granulosa cell; granulosa cell tumor; improved functioning; in vivo; infertile; microarray technology; mutant; necrocytosis; ontogeny; ovary disorder; overexpression; pathway; public health relevance; recombinase; response; social role; steroidogenesis; theca cell; transcription factor; unable to bear children
Relevance: The roles of the transcription factors GATA-4 and GATA-6 in folliculogenesis and fertility will be ad- dressed. These studies will contribute to better understanding of the cellular and molecular mechanisms that control ovarian function and improve our knowledge of the etiology of ovarian diseases such as granulosa cell tumors and infertility
Project start date: 2009-02-01
Project end date: 2014-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
5R01HD057110-03 (2010): $300757
Carlos Oscar Stocco
University Of Illinois At Chicago
Project start date: 2009-02-01
Project end date: 2014-01-31