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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD001041-04
Application #
2392309
Study Section
Population Research Committee (HDPR)
Project Start
1994-04-01
Project End
1999-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Bukulmez, O; Arici, A (2000) Leukocytes in ovarian function. Hum Reprod Update 6:15-Jan
Senturk, L M; Seli, E; Gutierrez, L S et al. (1999) Monocyte chemotactic protein-1 expression in human corpus luteum. Mol Hum Reprod 5:697-702
Arici, A; Senturk, L M; Seli, E et al. (1999) Regulation of monocyte chemotactic protein-1 expression in human endometrial stromal cells by estrogen and progesterone. Biol Reprod 61:85-90
Garcia-Velasco, J A; Arici, A (1999) Chemokines and human reproduction. Fertil Steril 71:983-93
Arici, A; Seli, E; Zeyneloglu, H B et al. (1998) Interleukin-8 induces proliferation of endometrial stromal cells: a potential autocrine growth factor. J Clin Endocrinol Metab 83:1201-5
Arici, A; Oral, E; Bahtiyar, O et al. (1997) Leukaemia inhibitory factor expression in human follicular fluid and ovarian cells. Hum Reprod 12:1233-9
Oral, E; Seli, E; Bahtiyar, M O et al. (1997) Growth-regulated alpha expression in human preovulatory follicles and ovarian cells. Am J Reprod Immunol 38:19-25