The long range of this project is to achieve an understanding of how hormones regulate normall genital tract development and how hormones elicit teratogenic effects. Particular emphasis is directed towards the role of epithelial-mesenchymal (E-M) interactions in hormone-induced epithelial development. In order to understand the adverse effects of exogenous estrogens on the development and differentiation of the human fetal genital tract, the ontogeny of estrogen (and progesterone), receptors will be assessed by autoradiography and immunocytochemistry. The effects of DES on the developing human prostate will be examined to determine whether DES causes irreversible changes in the expression of prostate-specific secretory markers (prostatic acid phosphatase, prostate specific antigen and peanut lectin binding sites). This project will entail an examination of the normal ontogeny of expression of these substances and their hormonal control. The abnormalities of ductal morphogenesis elicited by DES will be examined to determine whether DES perturbs the spatial pattern of epithelial DNA synthetic activity. Utilizing animal models, the role of epithelium in myometrial differentiation will be examined to determined whether only uterine epithelium can induce myometrial differentiation or whether other epithelium can induce uterine mesenchyme. The mechanism of epithelial effects on myometrial development will be assessed through use of transfilter culture assemblies in which epithelium and mesenchyme are grown on opposites sides of Nucleopore filters. The role of mesenchymal migration in myometrial differentiation will be assessed by microinjection of vitally dyed mesenchymal cells into the space between epithelium and mesenchyme. Finally, the last aspect of myometrial development will be to determine whether the DES- induced disruption of myometrial differentiation is due to direct estrogen receptor mediated events or via indirect, neuroendocrine imbalance, such as hyperprolactinemia. Utilizing uterine and vaginal epithelial inductions as model systems, the mechanism of these E-M interactions will be examined using transfilter protocols. This project utilizes antibodies to a cell surface heparan sulfate proteoglycan, cytokeratins, epithelial estrogen receptors, and new monoclonal antibodies as differentiation marker probes to assess the effects of mesenchyme on epithelial differentiation. Finally, the development of Mullerian (MD) and Wolffian duct (WD) epithelia will be examined to determined whether Mullerian Inhibiting Substance acts directly on the epithelium or via the surrounding mesenchyme. During the process of MD regression we will determine whether epthelial cells transform into fibroblasts. Lastly, cell attachment and spreading of MD and WD's will be examined to determine the types of extracellular matrix molecules (ECM) that are involved in these processes, to assess the role of hormones on attachment behavior, and to determine whether hormone-induced changes in epithelial attachment is due to direct or mesenchymally regualted processes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD017491-08
Application #
3314506
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1982-09-01
Project End
1992-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
8
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Lawrence, W D; Whitaker, D; Sugimura, H et al. (1992) An ultrastructural study of the developing urogenital tract in early human fetuses. Am J Obstet Gynecol 167:185-93
Cunha, G R; Young, P (1992) Role of stroma in oestrogen-induced epithelial proliferation. Epithelial Cell Biol 1:18-31
Cunha, G R; Alarid, E T; Turner, T et al. (1992) Normal and abnormal development of the male urogenital tract. Role of androgens, mesenchymal-epithelial interactions, and growth factors. J Androl 13:465-75
Cunha, G R; Battle, E; Young, P et al. (1992) Role of epithelial-mesenchymal interactions in the differentiation and spatial organization of visceral smooth muscle. Epithelial Cell Biol 1:76-83
Boutin, E L; Battle, E; Cunha, G R (1992) The germ layer origin of mouse vaginal epithelium restricts its responsiveness to mesenchymal inductors: uterine induction. Differentiation 49:101-7
Tsuji, M; Shima, H; Yonemura, C Y et al. (1992) Effect of human recombinant mullerian inhibiting substance on isolated epithelial and mesenchymal cells during mullerian duct regression in the rat. Endocrinology 131:1481-8
Cunha, G R; Young, P; Hamamoto, S et al. (1992) Developmental response of adult mammary epithelial cells to various fetal and neonatal mesenchymes. Epithelial Cell Biol 1:105-18
Cunha, G R; Young, P (1991) Inability of Tfm (testicular feminization) epithelial cells to express androgen-dependent seminal vesicle secretory proteins in chimeric tissue recombinants. Endocrinology 128:3293-8
Tsuji, M; Shima, H; Cunha, G R (1991) In vitro androgen-induced growth and morphogenesis of the Wolffian duct within urogenital ridge. Endocrinology 128:1805-11
Boutin, E L; Sanderson, R D; Bernfield, M et al. (1991) Epithelial-mesenchymal interactions in uterus and vagina alter the expression of the cell surface proteoglycan, syndecan. Dev Biol 148:63-74

Showing the most recent 10 out of 41 publications