MODULATION OF THE PI-PATHWAY IN PREGNANT MYOMETRIUM

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The phosphatidylinositol (PI) -signaling pathway plays an essential role during the intracellular signal transduction events occurring in nonexcitable cells in response to various hormones and neurotransmitters. Previous studies from my lahoratory have demonstrated that the PI- signaling pathway also plays a significant role during the generation of the cytosolic calcium oscillation-like phenomena that underlie phasic myometrial contractions. Phosphoinositidespecific phospholipase C (PI- PLC), protein kinase C (PKC), and diacylglycerol lipase (DAG-L), key enzymes involved in the PI-signaling pathway, are expressed in pregnant rat myometrium; expression that appears to be modulated during the latter third of gestation. Although temporaIly refated to the fall in progesterone and rise in estradiol occurring during the same period of gestation in the pregnant rat, the specific events responsible for the gestational modulation of these signal transduction enzymes are undefined. This study proposes to test the hypothesis that estradiol and/or progesterone specifically regulate the activity and expression of these key signal transduction enzymes in pregnant rat myometrium. The SPECIFIC MMS for this revised application are: 1) evaluate the effects of gestation and steroid hormones on the activity and expression of PI-PLC, 2) evaluate the effects of gestation and steroid hormones on the activity and expression of PKC, and 3) evaluate the effects of gestation and steroid hormones on the activity of the enzymes that metabolically inactivate DAG (ie. DAG-L and diacylglycerol kinase (DAG-K)). These studies will be performed utilizing rat myometrial tissue obtained during normal gestation, from pregnant rats undergoing steroid hormone manipulation in vivo, from pseudopregnant rats, and tissue cultures stimulated in vitro with steroid hormones. These proposed studies can be anticipated to clarify the effects of estradiol and progesterone on the PI -signaling pathway in pregnant myometrium; thereby further elucidating the hormonal regulation of the onset of parturition.