A study on EPPIN as a drug target for male contraception: developing a new animal model to test the efficacy of male contraceptive drugs

• Grant number: 15/08227-0
• Support Opportunities: Research Grants - Young Investigators Grants
• Duration: February 01, 2016 - January 31, 2021
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Erick José Ramo da Silva
• Grantee: Erick José Ramo da Silva
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Associated grant(s): 21/06718-7 - Translational studies on the sperm-binding protein EPPIN as a male contraceptive drug target, AP.JP2
• Associated scholarship(s): 19/16434-6 - Evaluation of sperm motility by CASA (Computer-Assisted Sperm Analysis) system, BP.TT; 19/13661-1 - Potential roles of EPPIN (Epididymal Protease Inhibitor) on post-testicular maturation of mouse spermatozoa: consequences for sperm function, BP.MS; 17/20102-3 - Regulation of expression of Wfdc (Whey-acidic protein four dissulfite core) genes by inflammatory stimulus in the mouse epididymis: potential roles on immune and reproductive functions, BP.MS; + associated scholarships 17/25982-1 - Impact of epididymitis induced by lipopolysaccharide from E. coli and lipotheicoic acid from S. aureus on the expression of genes involved in TLR4- and TLR2/TLR6-signaling pathways in the mouse epididymis, BP.IC; 17/11363-8 - EPPIN interacting proteins on mouse sperm surface: identification, expression and potential physiological roles, BP.MS; 16/23025-7 - Characterization of Eppin (Epididymal protease inhibitor) gene expression in mice, BP.IC - associated scholarships

Abstract

Nearly 50% of the pregnancies worldwide are unintended, which causes 80,000 maternal deaths every year due to unsafe abortions. This indicates there is an unmet need for new male contraceptive methods, which would facilitate family planning and promote family health. EPPIN (Epididymal protease inhibitor) is a promising target for male contraception due to its crucial role on reproduction and druggable properties. In humans, EPPIN is present on the surface of ejaculate spermatozoa, where it plays a role on sperm motility. In vitro studies showed that anti-EPPIN antibodies decreased progressive motility of human spermatozoa, indicating that sperm function can be inhibited by the pharmacological manipulation of EPPIN. To further develop EPPIN as a target for male contraceptive drugs a transition from in vitro to in vivo models is required. This would allow a deeper understanding on its physiological roles and facilitate the rational design of new EPPIN-binding drugs. Here, we propose to investigate the role of Eppin gene in the male fertility using the mouse as an experimental model. We will perform functional, molecular and protein-protein interaction assays to advance our knowledge regarding EPPIN´s role in reproduction and its potential as a therapeutic target for male contraception. Our results will provide the basis for the development of an animal model to evaluate the in vivo efficacy of male contraceptive drugs that inhibit sperm motility by binding to EPPIN, to shed light into the basic mechanisms by which EPPIN controls male fertility in vivo, and to provide new insights into the evolution of EPPIN gene. Our proposal has relevance and potential to innovate in the field of Pharmacology. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SILVA, ERICK J. R.; RIBEIRO, CAMILLA M.; MIRIM, ANDRE F. M.; SILVA, ALAN A. S.; ROMANO, RENATA M.; HALLAK, JORGE; AVELLAR, MARIA CHRISTINA W.. Lipopolysaccharide and lipotheicoic acid differentially modulate epididymal cytokine and chemokine profiles and sperm parameters in experimental acute epididymitis. SCIENTIFIC REPORTS, v. 8, JAN 8 2018. (15/08227-0)

SILVA, ALAN A. S.; RAIMUNDO, TAMIRIS R. F.; MARIANI, NOEMIA A. P.; KUSHIMA, HELIO; AVELLAR, MARIA CHRISTINA W.; BUFFONE, MARIANO G.; PAULA-LOPES, FABIOLA F.; MOURA, MARCELO T.; SILVA, ERICK J. R.. issecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: repercussions for male contraceptive developmen. MOLECULAR HUMAN REPRODUCTION, v. 27, n. 12, DEC 2021. (19/13661-1, 15/08227-0, 17/11363-8)

MARIANI, NOEMIA A. P.; CAMARA, ALINE C.; SILVA, ALAN ANDREW S.; RAIMUNDO, TAMIRIS R. F.; ANDRADE, JULIANA J.; ANDRADE, ALEXANDRE D.; ROSSINI, BRUNO C.; MARINO, CELSO L.; KUSHIMA, HELIO; SANTOS, LUCILENE D.; et al. Epididymal protease inhibitor (EPPIN) is a protein hub for seminal vesicle-secreted protein SVS2 binding in mouse spermatozoa. Molecular and Cellular Endocrinology, v. 506, APR 15 2020. (17/11363-8, 16/23025-7, 15/08227-0)

MUELLER, ANDRE; KIGUTI, LUIZ R. A.; SILVA, ERICK J. R.; PUPO, ANDRE S.. Contractile Effects of Serotonin (5-HT) in the Rat Cauda Epididymis: Expression and Functional Characterization of 5-HT Receptors. Journal of Pharmacology and Experimental Therapeutics, v. 369, n. 1, p. 98-106, APR 1 2019. (17/15175-1, 15/08227-0)

ANDRADE, ALEXANDRE D.; ALMEIDA, PRISCILA G. C.; MARIANI, NOEMIA A. P.; FREITAS, GEANNE A.; KUSHIMA, HELIO; FILADELPHO, ANDRE L.; SPADELLA, MARIA ANGELICA; AVELLAR, MARIA CHRISTINA W.; SILVA, ERICK J. R.. Lipopolysaccharide-induced epididymitis modifies the transcriptional profile of Wfdc genes in mice. BIOLOGY OF REPRODUCTION, v. 104, n. 1, p. 144-158, JAN 2020. (15/08227-0, 17/20102-3)

SIERVO, GLAUCIA ELOISA MUNHOZ DE LION; MARIANI, NOEMIA APARECIDA PARTELLI; SILVA, ALAN ANDREW S.; PUNHAGUI-UMBELINO, ANA PAULA FRANCO; DA COSTA, IVANA REGINA; DE ANDRADE, ALEXANDRE DORTH; SILVA, ERICK J. R.; FERNANDES, GLAURA SCANTAMBURLO ALVES. Low dose of cyclosporine A disrupts sperm parameters and testosterone levels reversibly in mice. Toxicology and Applied Pharmacology, v. 460, p. 9-pg., 2023-02-01. (15/08227-0)