The intrafollicular IGF-l system amplifies gonadotropin hormone action in granulosa cells. IGF-I alone or in combination with FSH can induce gonadotropin receptors, steroidogenic enzymes and promote follicular survival. The important interptay among IGF-I and FSH is underscored by the striking similarity of ovaries in IGF-I knockout, FSH knockout and FSH receptor knockout mice. The follicles in these mice are arrested in the early antral stage ol development. Whereas the mechanism of action of FSH is well known to involve the cAMP/protein kinase A signaling pathway, almost nothing is known about the intracellular actions of IGF-I in the ovary. Furthermore, recent studies by others and our preliminary data suggest that some of the signaling pathways utilized by IGF-I and FSH converge. The proposed studies are designed to test the overall hypothesis that IGF-I induced P1-3-kinase signaling pathway is required for granulosa cell survival and amplification of FSH-induced granulosa cell differentiation. The specific questions to be answered in this proposal are:
Aim 1) Are the signaling events initiated by IGF-I amplified in response to FSH? Hypothesis: The IGF-I dependent P1-3-kinase signaling pathway in granulosa cells is augmented by FSH.
Aim 2) Are the survival effects of IGF-I and FSH mediated by parallel or converging intracellular signaling pathways? Hypothesis I: The survival effects of IGF-I and FSH are mediated by P1-3-kinase/Akt mediated phosphorylation of Bad. Hypothesis II: IGF-I and FSH elevate the cellular ratio of antiapoptotic (e.g., Bc12, Bcl-Xlong, Mci-I) to pro -apoptotic proteins (e.g., Bad, Bax, Bok) and inhibit caspase activity.
Aim 3) Is FSH directed granulosa cell differentiation mediated via IGF-I dependent signaling systems? Hypothesis: IGF-I stimulated P1-3-kinase signaling events amplifies FSH directed expression of differentiation, whereas ERK signaling represses djfferentiation. We will employ specific chemical inhibitors and adenovirus vectors that express dominant negative or active signaling molecules to dissect the IGF-I and FSH directed signaling pathways that are responsible for granulosa cell survival or granulosa cell differentiation. Further characterization of the IGF-I and FSH signaling events and their interactions are likely to provide new insights into how multiple genes are coordinately regulated by trophic factors during follicle development. Our studies are expected to translate into more effective treatments for controlling follicle selection and development, ovulation and fertility. This new insight may uncover mechanistic defects that underlay disorders of folliculogenesis, premature ovarian failure and disorders such as polycystic ovarian syndrome.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
3R01HD038813-02S1
Application #
6597956
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Taymans, Susan
Project Start
2001-05-01
Project End
2005-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$6,542
Indirect Cost
Name
University of Nebraska Medical Center
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Henkes, Luiz E; Sullivan, Brian T; Lynch, Maureen P et al. (2008) Acid sphingomyelinase involvement in tumor necrosis factor alpha-regulated vascular and steroid disruption during luteolysis in vivo. Proc Natl Acad Sci U S A 105:7670-5
McDonald, Claudia A; Millena, Ana C; Reddy, Sheila et al. (2006) Follicle-stimulating hormone-induced aromatase in immature rat Sertoli cells requires an active phosphatidylinositol 3-kinase pathway and is inhibited via the mitogen-activated protein kinase signaling pathway. Mol Endocrinol 20:608-18
Arvisais, Edward W; Romanelli, Angela; Hou, Xiaoying et al. (2006) AKT-independent phosphorylation of TSC2 and activation of mTOR and ribosomal protein S6 kinase signaling by prostaglandin F2alpha. J Biol Chem 281:26904-13
Davis, John S; Rueda, Bo R; Spanel-Borowski, Katherina (2003) Microvascular endothelial cells of the corpus luteum. Reprod Biol Endocrinol 1:89
Henkes, Luiz E; Davis, John S; Rueda, Bo R (2003) Mutant mouse models and their contribution to our knowledge of corpus luteum development, function and regression. Reprod Biol Endocrinol 1:87
Chen, Dong-bao; Davis, John S (2003) Epidermal growth factor induces c-fos and c-jun mRNA via Raf-1/MEK1/ERK-dependent and -independent pathways in bovine luteal cells. Mol Cell Endocrinol 200:141-54
Pru, James K; Lynch, Maureen P; Davis, John S et al. (2003) Signaling mechanisms in tumor necrosis factor alpha-induced death of microvascular endothelial cells of the corpus luteum. Reprod Biol Endocrinol 1:17