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EPPIN as a binding site for the seminal plasma protein SVS2 on mouse spermatozoa: effects on capacitation, mechanism of action and applications in male contraception

Grant number: 23/04496-2
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): May 01, 2023
Effective date (End): September 30, 2027
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Erick José Ramo da Silva
Grantee:Natália Calixto Miranda Santos
Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Associated research grant:21/06718-7 - Translational studies on the sperm-binding protein EPPIN as a male contraceptive drug target, AP.JP2

Abstract

Mammalian spermatozoa require a last maturation step in the female reproductive tract to fertilize the egg. This remarkable physiological process, known as capacitation, prepares spermatozoa to undergo acrosome reaction (AR). At the molecular level, activation of the adenylyl cyclase/cyclic AMP/protein kinase A (AC/cAMP/PKA) pathway and phosphorylation cascades and hyperpolarization of the plasma membrane potential (Em) occur in capacitating spermatozoa. Seminal plasma proteins belonging to the REST (rapidly-evolving seminal vesicle transcribed) family, such as human SEMG1 and its mouse ortholog SVS2, inhibit sperm capacitation via mechanisms still poorly understood. We recently demonstrated that the sperm protein EPPIN is a docking site for SVS2 on mouse spermatozoa. Due to its roles in sperm function and druggable properties, EPPIN is a sperm drug target for male contraception. In this study, we will test the hypothesis that SVS2 inhibits sperm capacitation upon binding EPPIN. We will evaluate the effects of recombinant SVS2 fragments (full-length and truncations containing or not the EPPIN-binding sequences) on AR in spermatozoa from wild-type and transgenic mice. To study the mechanisms underlying the effects of EPPIN/SVS2 interaction on sperm capacitation, we will investigate whether recombinant SVS2 isoforms affect in vitro fertilization rates and capacitation-induced protein phosphorylation, cAMP production, and Em hyperpolarization. We expect to provide insights into the mechanisms by which EPPIN interactions with REST proteins regulate male fertility, opening new paths to male contraceptive drug development targeting spermatozoa. (AU)

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