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Investigating the mechanism of action and function of innate immunity components in the morphogenesis of the epididymis

Grant number: 19/02633-7
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2019
Effective date (End): December 31, 2019
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Maria Christina Werneck de Avellar
Grantee:Fernanda Akane Nishino
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The epididymis is an essential organ of the male reproductive system for the maturation, transport and storage of a viable spermatozoa for oocyte fertilization. Its embryonic precursor, the mesonephric duct (or Wolff's duct), differentiates through tubular-epithelial morphogenesis that is primarily induced and dependent on androgens. Thus, abnormalities of this event can result in infertility later in postnatal and adult life. It is known that the postnatal and adult epididymis from different species presents cellular and molecular components of the innate immunity that are part of epididymis immunobiology. Among them, the ²- defensing family of antimicrobial proteins that are also multifunctional modulators abundantly expressed in the epididymis epithelium. Several epididymis ²-defensing are targets of androgen modulation, and participate in events required for sperm function. Recently, our group has pointed out for the first time that the ²-defensing SPAG11C (sperm associated antigen 11C) and hDEFB2 (recombinant human ²-defensing 2) can act as androgen-dependent mediators during rat epididymis prenatal development. Their mechanism of action and biological roles on epididymis morphogenesis are under investigation. One hypothesis is DEFB2 playing a role via TLR4 (Toll-like receptor 4) cellular signaling. To test this hypothesis, we propose in this project: a) to evaluate the TLR4 immune distribution in mesonephric ducts from rat fetuses; b) to characterize the cellular and molecular effects of recombinant hDEFB2 and the activation of TLR4 signaling in organotypic cultures of rat mesonephric ducts; and c) to evaluate the intracellular trafficking/secretion pattern of hDEFB2 (transient expression assays in cell culture), as well as the ability of this protein to bind lipopolysaccharide (LPS; circular dichroisms assays). The results will be relevant to a better understanding of the role of components of innate immunity in epididymis morphogenesis.