Estradiol, has been shown to interact with specific receptors in target cells resulting in the stimulation of gene expression. Cell culture models (eg. human breast cancer cell lines) have made valued contributions to the understanding of the molecular mechanisms involved in this process. However, in vivo responses are more complicated since responsive tissues such as the uterus are composed of at least three resident cell types (epithelial, stromal and myometrial) each of which can express different responses to steroids. Furthermore, the administration of estradiol to rats results in a specific, estrogen dependent influx of leukocytes, especially eosinophils into the uterus. There is approximately a 50 - fold increase in the number of eosinophils in the uterus following stimulation with estradiol. This increase has been shown to be regulated through the normal estrous cycle of the rat reaching a maximum of 8,000,000 eosinophils at estrus from a low of 150,000 at diestrus. Similar increases have been seen in the post-partum uterus. The presence of an eosinophil chemotactic factor has been documented in the uterus (ECF-U). This factor is stimulated by estrogens through a receptor mediated mechanism and further regulated through the interaction of progestins and glucocorticoids. The proposed research will focus on two aspects regarding this chemotactic factor. Firstly, the nature of ECF-U will be examined, this will be accomplished through the isolation and characterization of the factor and cloning of ECF-U cDNA. Secondly, the cellular origin and molecular mechanisms of regulation of ECF-U expression will be examined. The infiltration of eosinophils, as in the case of lungs of patients with asthma, has been associated with epithelial cell damage or death. In the reproductive tract eosinophils or eosinophil homologous proteins have been associated with tissue remodeling during; the normal rat estrous cycle, implantation, and regression of the post-partum uterus. We hypothesize that uterine eosinophils play a role in tissue remodeling. This hypothesis will be tested by examining uterine growth and function in the absence of eosinophil infiltration. The infiltration of eosinophils will be prevented by treatment of rats with neutralization antibodies against ECF-U which prevent chemotaxis. These studies will result in a sound understanding of the nature of ECF-U and the mechanisms which control eosinophil infiltration. They will also provide new information as to the regulation of uterine function and mechanisms of steroid regulation in an integrated system.
Showing the most recent 10 out of 34 publications
