The human endometrium undergoes regular intervals of proliferation and secretory maturation throughout the normal menstrual cycle. Though physiological parameters regulating menstrual cyclicity have been well-characterized, the cellular and molecular aspects of this dynamic process remain unclear. Both morphologic and physiologic observations have illustrated the possibility that direct (via contact) or indirect (via secreted factors) communication between endometrial stromal and epithelial cells may be an integral part of the regulatory process. Furthermore, recent advances in our understanding of the role of growth factors in a variety of tissues suggests they comprise the primary language by which stromal and epithelial cells communicate. Considerable attention of numerous investigators has been on the epidermal growth factor family (including transforming growth factor-alpha) in the regulation of cellular proliferation. Experiments in this grant application will focus on transforming growth factor-beta (TGF-beta), and the potential roles it plays in the regulation of normal human endometrial stromal and epithelial growth and differentiation. Using an established in vitro model of isolated human endometrial cell populations, the production of TGF-beta by epithelial and stromal cells throughout the normal menstrual cycle will be examined. Additionally, the direct effects of TGF-beta on isolated endometrial epithelial and stromal cells will be examined using established methodology to monitor cell proliferation (bromodeoxyuridine uptake) and differentiation (expression of stage-specific marker epitopes). Finally, the regulation of TGF-beta production and response by endometrial epithelial and stromal cells in response to specific hormonal stimulation will be explored. Completion of the specific aims proposed in this application should provide insight into the cellular and molecular interactions directing endometrial proliferative and maturational events under the influence of a changing hormonal milieu.
