The cyclic process of ovarian folliculogenesis is an exponential rather than a linear process marked by dramatic proliferation and differentiation of the developing granulosa cell. Although the central role(s) of gonadotropins and of gonadal steroids in this explosive agenda is well accepted, the variable fate of follicles afforded comparable gonadotropic stimulation suggests the existence of additional intraovarian modulatory systems. Amongst potential novel intraovarian regulators, Somatomedin-C/Insulin-like growth factor I (referred to herein as IGF-I) has been the subject of increasingly intense investigation. Considered in aggregate, these studies strongly suggest the existence of an intraovarian autocrine control mechanism, wherein IGF-I may serve as the central signal, and the granulosa cell its site of production, reception, and action. In this capacity, IGF-I may promote the replication and/or cytodifferentiation of the developing granulosa cell, acting largely (but not exclusively) as an amplifier of gonadotropin action. To further evaluate the potential relevance of IGF- I to ovarian physiology, a series of studies are proposed on the developmental control, hormonal regulation, and cellular localization of ovarian IGF-I and its receptor. In this connection, parallel measurements of the corresponding gene transcripts as well as of their presumptive protein products will be carried out. Continued attention will be paid to the cellular mechanism(s) and site(s) of IGF-I action in the granulosa cell, concentrating on the role(s) of G proteins of the adenylate cyclase complex as well as on the involvement of cAMP-dependent protein kinase. Lastly, we propose, for the first time, to study the characteristics, role and regulation of a functional granulosa cell- generated IGF-I binding protein, an exciting development concerned with the amplification of IGF-I and hence gonadotropin action. The long term goal of this investigation is to develop an understanding of the molecular mechanism(s) by which IGF-I may participate in the organization of the follicular apparatus and in the control of its growth and differentiation. Such studies should include an evaluation of the significance of IGF-I to intraovarian paracrine interactions and the provision of irrefutable in vivo evidence for its role in normal ovarian physiology.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD019998-08
Application #
3317745
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1985-04-01
Project End
1993-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Hourvitz, A; Widger, A E; Filho, F L et al. (2000) Pregnancy-associated plasma protein-A gene expression in human ovaries is restricted to healthy follicles and corpora lutea. J Clin Endocrinol Metab 85:4916-20
Kol, S; Ruutiainen-Altman, K; Scherzer, W J et al. (1999) The rat intraovarian interleukin (IL)-1 system: cellular localization, cyclic variation and hormonal regulation of IL-1beta and of the type I and type II IL-1 receptors. Mol Cell Endocrinol 149:115-28
Resnick, C E; Fielder, P J; Rosenfeld, R G et al. (1998) Characterization and hormonal regulation of a rat ovarian insulin-like growth factor binding protein-5 endopeptidase: an FSH-inducible granulosa cell-derived metalloprotease. Endocrinology 139:1249-57
Ando, M; Kol, S; Kokia, E et al. (1998) Rat ovarian prostaglandin endoperoxide synthase-1 and -2: periovulatory expression of granulosa cell-based interleukin-1-dependent enzymes. Endocrinology 139:2501-8
Ben-Shlomo, I; Kol, S; Roeder, L M et al. (1997) Interleukin (IL)-1beta increases glucose uptake and induces glycolysis in aerobically cultured rat ovarian cells: evidence that IL-1beta may mediate the gonadotropin-induced midcycle metabolic shift. Endocrinology 138:2680-8
Choi, D; Rohan, R M; Rosenfeld, R G et al. (1997) Activin-attenuated expression of transcripts encoding granulosa cell-derived insulin-like growth factor binding proteins 4 and 5 in the rat: a putative antiatretic effect. Biol Reprod 56:508-15
Kol, S; Ben-Shlomo, I; Ando, M et al. (1997) Insulin-like growth factor I affects the intraovarian interleukin-1 system: evidence for suppression of type I interleukin-1 receptor expression and enhancement of secretory phospholipase A2 expression and activity. Mol Hum Reprod 3:1095-9
Kol, S; Ruutiainen-Altman, K; Ben-Shlomo, I et al. (1997) The rat ovarian phospholipase A2 system: gene expression, cellular localization, activity characterization, and interleukin-1 dependence. Endocrinology 138:322-31
Adashi, E Y; Resnick, C E; Payne, D W et al. (1997) The mouse intraovarian insulin-like growth factor I system: departures from the rat paradigm. Endocrinology 138:3881-90

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