The general question addressed in this project is: how do sex steroid hormones cause maturation of reproduction organs? A model system for the study of this question is the immature female rat. When such a rat is given an injection of estradiol (E2), a very rapid development of the uterus ensues. One of the first detectable biochemical changes is an increase in two proteins - tissue factor (TF) and thrombin. Because they are among the first things to change, it seems possible or even likely that they may be involved in the further development of the uterus - that E2 activates them, and they in turn activate other developmental processes. Both proteins are associated with cell division in other biological systems. When the smooth muscle cells lining blood vessels are stimulated to grow, increases in TF occur. Thrombin is a stimulator of cell division in fibroblast and may be important in the process of wound healing. Since both proteins are present in the uterus as it begins to grow they may be involved with uterine development under the control of E2 . Our investigations are directed at proving this hypothesis. Our studies are complicated by the fact that thrombin is generated in biological systems from a precursor - prothrombin - by the enzymes of the coagulation cascade which begins with TF. A question we must answer is whether TF acts as a growth factor per se or as the initiator of thrombin generation through the coagulation cascade. The aims of this project are: 1) to show that thrombin causes cell division in the uterus after E2 stimulation and 2) to find out whether TF acts directly on the uterus or indirectly by the generation of thrombin. This research will increase our understanding of a normal biological process - the maturation of one of the organs of reproduction.//
