Signal Transduction Laboratory

Overview

Director: John S. Davis, Ph.D.

The fertility of humans and domestic livestock is steadily decreasing. Many women’s health issues are linked to changes in reproductive hormones. Our studies to understand the basic physiological processes that regulate the differentiation of ovarian cells and the production of steroid hormones will allow new strategies to improve fertility, prevent early pregnancy losses, and develop more effective contraceptives. We are also examining the possibility that elevated blood levels of highly glycosylated pituitary hormones may contribute to osteoporosis during menopause. Additionally, our studies to understand the mechanisms that control ovarian angiogenesis and ovarian cancer may lead to the development of new therapies for the treatment of this deadly disease.

Our research studies the physiological events and molecular mechanisms that regulate the cyclical function of the ovary and its pathologies, such as steroid synthesis and ovarian cancer. These processes are controlled by the actions of various hormones and growth factors that initiate a complex pattern of intracellular signaling events. Unraveling these signaling events is our passion and will provide important clues for therapeutic interventions to improve women’s health.

One thrust of our laboratory is to characterize the intracellular signaling systems that mediate the growth and differentiating properties of the pituitary gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH). FSH regulates follicle growth, differentiation, and estrogen secretion. LH is responsible for stimulating ovulation, corpus luteum development, and the maintenance of progesterone and peptide secretion. Both hormones activate distinctive cascades of intracellular signals that stimulate cell proliferation, cell survival, and gene expression. These signaling cascades involve the activation of enzymes that phosphorylate proteins or lipids such as tyrosine protein kinases, serine/threonine protein kinases (PKA, PKB (Akt), PKC, MAPK, Akt, mTOR, etc), and lipid kinases such as phosphatidylinositol 3-kinase (PI 3-kinase). Knowledge of these signaling mechanisms is crucial to fully understand the mechanisms that promote fertility and regulate ovarian steroidogenesis. Ovarian steroids, in addition to their role in reproduction, play a prominent role in the regulation of other aspects of women’s health, including bone mineralization and cardiovascular disease. Another thrust of this laboratory is to understand how growth factors and cytokines regulate ovarian function. Specific growth factors, such as insulin-like growth factor-I (IGF-I), promote cell proliferation and augment the action of gonadotropins. This involves activation of growth factor receptors, tyrosine kinases, PI 3-kinase and inhibition of programmed cell death (apoptosis). In contrast, environmental stresses and cytokines such as transforming growth factor beta (TGFb), tumor necrosis factor alpha (TNFa), Fas ligand (FasL) and interferon gamma (IFNg) interfere with cell growth, promote cell death, prevent differentiation, and inhibit steroidogenesis. The identification of signaling elements that interfere with gonadotropin action may provide important clues to critical links in the regulation of fertility, menopause, and aging.

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