Macrophages and granulocytes are present in reproductive tissues where they participate in and affect many aspects of ovarian and u tetrine function. The hypothesis to be tested in this proposal is that leukocyte migration in the ovaries is hormonally regulated and this regulation occurs through modulation of chemotactic factors. Based on the applicant's preliminary results the focus of this research will be study the physiologic relevance of chemotactic factors for the recruitment and activation of macrophages and neutrophils in the ovary. Regulation of the traffic of leukocytes by chemoattractant, such as interleukin-8 that acts on neutrophils and monocyte chemotactic protein-1 that acts on monocyte/macrophages, followed by the secretion of specific paracrine factors by the leukocytes may be one of the ways by which certain reproductive events such as ovulation and luteal function are controlled. Based on our hypothesis, the long-range goal of this research is to define bimolecular events modulating the expression of these factors in humans. To accomplish this goal and to provide optimal opportunity for the applicant to perfect the investigative skills necessary for independent research, we propose three specific aims as follows:
Specific Aim 1. To identify and characterize the functional significance of specific chemotactic factors (IL-8 and MCP-1) in reproductive physiology using a rodent model.
Specific Aim 2. To identify and characterize in humans the presence and variations of the expression of these chemoattractant (IL-8 and MCP-1) in the ovaries throughout the menstrual cycle and during pregnancy.
Specific Aim 3. To investigate the in vitro regulation of the expression of these chemoattractant by gonadal steroid hormones, growth factors and cytokines. A definition of the bimolecular events related to chemoattraction of migratory cells relevant to ovulation and luteal function will be important in advancing our understanding of these aspects of reproductive biology. We believe that series of focused investigations that explore the physiologic relevance of the chemoattractant factors in regulating the chemotaxis and activation of macrophages and neutrophils in reproductive tissues may reveal new insights into the etiology of ovulatory dysfunctions, infertility and early pregnancy losses.
