The long term objective of this research is to advance our understanding of the occurrence of endometriosis and the associated infertility. The research will focus on the cause of the infertility associated with this disease. Many past studies have indicated that the peritoneal fluid of women with endometriosis contains approximately ten times the number of macrophages as is seen in the disease free fertile patient. Further studies have strongly indicated that these activated macrophages can display several activities which are deleterious to successful reproduction. The central focus of this study will be the identification of the mechanism responsible for the directed migration or chemotaxis of macrophages to the peritoneum. Preliminary data have demonstrated a significant increase in the concentration and activity of a macrophage chemotactic factor in the peritoneal fluid of patients suffering from endometriosis, when compared with normal fertile controls or patients on medical treatments. Further studies have indicated that this chemotactic activity is normally expressed in the stromal cells of the luteal phase and is absent in the proliferative phase. However, in patients with endometriosis the proliferative phase endometrium demonstrates high chemotactic activity. The overall specific aim of this study is to elucidate the possible mechanism(s) by which this factor modulates the number and activity of peritoneal macrophages in women with endometriosis.
The specific aims are to isolate and characterize this factor through protein purification, N-terminal amino acid sequence analysis and CDNA cloning. The cells responsible for the production of this factor will be determined through immunohistochemical analysis and protein synthesis. The regulation of this factor in the endometriotic tissue and in the normal endometrium will be examined through protein synthesis and RNA analysis. In addition to the mechanism(s) responsible for the expression of this factor studies will also be performed to determine the mechanism by which this factor interacts with macrophages. These studies will examine the ability of this factor to activate macrophages as well as direct their migration. Chemotactic factor/macrophage interaction will also be examined at the level of cell surface receptors. Studies will be directed at the characterization of the receptor through isolation and expressing cloning. Our hypothesis suggests that there exists a macrophage chemotactic factor which is inappropriately expressed in women with endometriosis. Furthermore, this chemotactic factor can activate macrophages through binding to a specific cell surface receptor. These results will define the mechanism involved in the infiltration of macrophages into the peritoneum. A solid understanding of the nature of the chemotactic factor, the regulation of its expression, and the mechanism by which it interacts with macrophages will open new possibilities for the development of therapies for the treatment of endometriosis and the associated infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD030475-02
Application #
2202810
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1992-09-30
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1995-08-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104