Abstract

Phosphoinositide-specific phospholipase C (PI-PLC) plays an essential role during intracellular signal transduction in myometrium in response to uterotonic hormones (eg. oxytocin). Recent reports have confirmed that PI- PLC also plays an important role in the development and maintenance of cytosolic calcium oscillations occurring in many different cell types in response to hormone receptor occupancy. As discussed in the preliminary data, studies performed in my laboratory have provided compelling support for the hypothesis t at myometrial contractions occur in response :t,o oxytocin stimulated cytosolic calcium oscillations. This data also suggests that PI-PLC plays an essential role in the biochemical events resulting in cytosolic calcium oscillations and myometrial contractions. The research being proposed in this application will test the hypothesis that oxytocin stimulates the G-protein/PI-PLC complex, resulting in cytosolic calcium oscIllations which drive phasic myometrial contractions.
The specific aims are as follows: 1) evaluate the effects of uterotonic agonists and PI-PLC inhibitors on cytosolic calcium oscillations and phasic myometrial contractions, 2) elucidate the role of inositol 1,4,5- trisphosphate during cytosolic calcium oscillations and phasic myometrial contractions, 3) evaluate the role of calcium-induced calcium release (CICR) during PI -PLC induced calcium oscillations and phasic myometrial contractions, and 4) evaluate the role of extracellular calcium during PI- PLC induced calcium oscillations and phasic myometrial contractions. The proposed studies will be performed utilizing myometrial tissue obtained from pregnant Sprague-Dawley rats on specific days of gestation. These studies will provide, for the first time, an intracellular mechanism explaining how oxytocin stimulation results in the development of phasic myometrial contraction.Characterization of these signal transduction mechanisms in myometrium will significantly improve our understanding of basic mechanisms occurring during parturition, and facilitate the development of effective pharmacologic agents to treat disturbances of labor (eg. premature labor).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD028506-02
Application #
2201155
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1994-09-01
Project End
1997-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
University of Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

Phillippe, Mark; Sweet, Leigh M; Bradley, Diana F et al. (2009) Role of nonreceptor protein tyrosine kinases during phospholipase C-gamma 1-related uterine contractions in the rat. Reprod Sci 16:265-73
Phillippe, Mark; Sweet, Leigh M; Engle, Daniel (2007) The role of phospholipase Cgamma1 tyrosine phosphorylation during phasic myometrial contractions. Am J Obstet Gynecol 196:179.e1-7
Phillippe, Mark; Bradley, Diana F; Engle, Daniel et al. (2006) SHP protein tyrosine phosphatase expression in rat uterine tissue. J Soc Gynecol Investig 13:338-42
Chien, Edward K; Sweet, Leigh; Phillippe, Mark et al. (2003) Protease-activated receptor isoform expression in pregnant and nonpregnant rat myometrial tissue. J Soc Gynecol Investig 10:460-8
Phillippe, Mark; Wolff, David; Saunders, Trevania et al. (2002) Intrauterine expression of prothrombin in the sprague-dawley rat. J Soc Gynecol Investig 9:276-81
Phillippe, M; Elovitz, M; Saunders, T (2001) Thrombin-stimulated uterine contractions in the pregnant and nonpregnant rat. J Soc Gynecol Investig 8:260-5
Elovitz, M A; Ascher-Landsberg, J; Saunders, T et al. (2000) The mechanisms underlying the stimulatory effects of thrombin on myometrial smooth muscle. Am J Obstet Gynecol 183:674-81
Elovitz, M A; Saunders, T; Ascher-Landsberg, J et al. (2000) Effects of thrombin on myometrial contractions in vitro and in vivo. Am J Obstet Gynecol 183:799-804
Ascher-Landsberg, J; Saunders, T; Elovitz, M et al. (1999) The effects of 2-aminoethoxydiphenyl borate, a novel inositol 1,4, 5-trisphosphate receptor modulator on myometrial contractions. Biochem Biophys Res Commun 264:979-82
Ascher-Landsberg, J; Saunders, T; Phillippe, M (1999) Tyrosine kinase-mediated activation of cytosolic calcium oscillations and phasic myometrial contractions. J Soc Gynecol Investig 6:240-4

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