Research Project
2872812
The major goal of this research is to increase our understanding of the mesenchymal-epithelial interactions that mediate estrogen/progestin action in the nonhuman primate female reproductive tract. In the previous period we found two soluble mediators that may function as hormonally regulated paracrine agents in the tract. These mediators are stromally-derived growth factors, namely Keratinocyte Growth Factor (KGF) and Hepatocyte Growth Factor (HGF). They and their receptors are present in the primate reproductive tract and they are hormonally regulated. In the endometrium, HGF is upregulated by estradiol, and we hypothesize it acts as an estromedin, while KGF is upregulated by P and we hypothesize that it acts as a progestomedin. However, in the oviduct and cervix, preliminary data indicate that both HGF ink KGF are upregulated by estradiol, which indicates different modes of hormonal regulation in different regions of the tract. We have also found that the stromelysins, a family of matrix metalloproteinases, mostly secreted by stromal cells, are upregulated by P-withdrawal in the primate endometrium. These enzymes could play dramatic roles in the onset of menstruation, the repair of the endometrial surface, and the subsequent glandular remodeling that occurs during the early proliferative phase. These enzymes have been implicated wherever tissue remodeling occurs, yet little is known about their function in the reproductive tract. We hypothesize that they play key roles in the extensive remodeling that occurs every cycle. We propose two strategies to gain new understanding of how these stromal growth factors affect the physiology of the reproductive tract. First we will evaluate their cellular localization and hormonal regulation with biochemical, hybridization, and immunocytochemical techniques, and second, we will evaluate their physiological significance by both systemic administration and local intraluminal intrauterine infusion techniques. The work has 4 specific aims, namely to investigate, in the rhesus monkey female reproductive tract, the following: Aim 1. The hormonal regulation and localization of the HGF/c-MET paracrine system; Aim 2. The hormonal regulation and localization of KGF/KGFR paracrine system; Aim 3. The hormonal regulation and localization of the matrix metalloproteinases; and Aim 4. The effects of both local and systemic administration of the above growth factors on the reproductive tract.
