The objective of this proposal is to explore the hypothesis that expression of matrix metalloproteinases (MMPs) is causally involved in the establishment or maintenance of human endometriosis. Because MMPs are enzymes thought to be agents of the controlled degradation of extracellular matrix, which occurs during normal tissue development, the regulation of their expression and activity is likely a fundamental process in normal as well as pathological endometrial tissue growth. Our experimental plan is to determine whether the expression and activity of MMPs in normal and endometriotic endometrial tissues supports a causal role for abnormal MMP regulation in human endometriosis. This will be accomplished: by identifying the normal and pathological patterns of expression of MMPs and tissue inhibitors of MMPs (TIMPs) during the reproductive cycle, using in situ hybridization, immunohistochemical and other techniques; by examining the hormonal regulation of expression MMPs and TIMPs by using an in vitro model of normal endometrium and endometriotic human tissues; by studying the cellular and tissue functions of MMPs and TIMPs by determining the effects of inhibition of MMP expression or activity on the growth patterns of cultured human endometrial and endometriotic tissues by using TIMPs, immunologic and antisense techniques to inhibit MMP expression or activity in vitro, and by developing a nude mouse model of implantation of human endometriotic tissue into peritoneum to test the effect of manipulation of MMP expression on possible initiating events in endometriosis. Data generated from these studies will provide useful information on expression of MMPs in normal endometrium and endometriotic implants. Data on the hormonal regulation of expression of these enzymes may be used to design novel therapeutic approaches to control growth of normal endometrium and endometriotic implants. It is also likely that the principles of MMP regulation discovered in the course of these experiments will be applicable to the understanding and control of the processes of normal and pathological tissue growth in other tissues.
