The long-term goals of this research project are to understand the function of Eppin: its interaction with binding partners in a molecular complex on the sperm surface, its relationship with prostate specific antigen (PSA), and its role during the resumption of sperm motility following ejaculation. Very few molecular details are known about the protein-protein interactions that occur on the sperm surface immediately after ejaculation in humans when the resumption of full motility is critical for fertility. As a novel approach to understanding male gamete biology at this critical step, the revised research proposal will seek to understand the interaction of Eppin with its binding partners and its receptor(s) on the human sperm surface, particularly with regard to the resumption of sperm motility following ejaculation.
Specific aim #1 will characterize the Eppin protein complex found on the surface of human spermatozoa. Eppin and semenogelin are associated with two other surface proteins, namely clusterin and lactoferrin. Therefore in the discovery phase of this project, specific aim #1 will describe this complex in detail and test our hypothesis that anti-Eppin antibodies will disrupt the Eppin protein complex.
Specific aim #2 will identify and characterize the receptor(s) on spermatozoa for Eppin and the Eppin protein complex described in aim #1. Our hypothesis is that Eppin and its complex has a sperm receptor or receptors and their identity will lead to a better understanding of Eppin's function within the complex.
Specific aim #3 will characterize the human prostate specific antigen (PSA)-Eppin interaction and its influence on sperm motility. Our discovery that recombinant Eppin modulates PSA enzyme activity in the human ejaculate leads us to propose the hypothesis that Eppin-PSA interaction affects the hydrolysis of semenogelin by PSA and is therefore of physiological relevance immediately after ejaculation as progressive motility begins.
This aim will test the hypothesis that anti-Eppin antibodies disrupt Eppin's modulation of PSA activity.
|O'Rand, Michael G; Widgren, Esther E (2012) Loss of calcium in human spermatozoa via EPPIN, the semenogelin receptor. Biol Reprod 86:55|
|Silva, Erick J R; Hamil, Katherine G; Richardson, Richard T et al. (2012) Characterization of EPPIN's semenogelin I binding site: a contraceptive drug target. Biol Reprod 87:56|
|O'Rand, Michael G; Widgren, Esther E; Hamil, Katherine G et al. (2011) Functional studies of eppin. Biochem Soc Trans 39:1447-9|
|O'Rand, Michael G; Widgren, Esther E; Hamil, Katherine G et al. (2011) Epididymal protein targets: a brief history of the development of epididymal protease inhibitor as a contraceptive. J Androl 32:698-704|
|Mitra, Anurag; Richardson, Richard T; O'Rand, Michael G (2010) Analysis of recombinant human semenogelin as an inhibitor of human sperm motility. Biol Reprod 82:489-96|
|O'Rand, Michael G; Widgren, Esther E; Beyler, Stan et al. (2009) Inhibition of human sperm motility by contraceptive anti-eppin antibodies from infertile male monkeys: effect on cyclic adenosine monophosphate. Biol Reprod 80:279-85|
|Wang, Zengjun; Widgren, E E; Richardson, R T et al. (2007) Eppin: a molecular strategy for male contraception. Soc Reprod Fertil Suppl 65:535-42|
|Wang, Zengjun; Widgren, Esther E; Richardson, Richard T et al. (2007) Characterization of an eppin protein complex from human semen and spermatozoa. Biol Reprod 77:476-84|