Molecular and genetic mechanisms of sperm capacitation

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DESCRIPTION (provided by applicant): Mammalian sperm are released by the male in an infertile state, and acquire the ability to fertilize through a physiological reprogramming, or "capacitation", which occurs with the female reproductive tract. Capacitation is associated with diverse modifications in the biochemical and biophysical properties of sperm, and leads to diverse changes in the behavioral repertoire of that cell. However, available evidence indicates that capacitation is not a unitary event, but instead is the sum of a series of component reactions that differ in time course and in mode of regulation. The challenge at present, and the long-term foal of this new project, is to prepare a linkage map of sperm signal transduction, in which specific component reactions are related to upstream activators and to downstream functional changes. This phase focuses on the role of pkdrej, a polycystin-1 protein, in capacitation. Targeted deletions of the pkdrej gene produce a slowing of select aspects of capacitation and in the failure of a chemosensory response of sperm to oviduct fluid. Polycystin-1 proteins are believed to function as ligand- or mechanically-activated receptors that activate signaling pathways. A similar role is proposed in sperm, in which pkdrej acts as a receptor for a capacitating signal. The specific aims for the first stage of this work are: 1) to identify intracellular effectors that mediate pkdrej signal transduction; 2) to determine the mechanism by which pkdrej controls the elevation of sperm internal pH; 3) to analyze the mechanism of motility regulation by pkdrej; and 4) to identify the sperm proteins that are phosphorylated in a pkdrej-dependent manner during capacitation. The public health significance of this project is in two related areas. In an era of potentially catastrophic population growth it is necessary to identify new strategies of contraception. Given the essential role of capacitation in fertilization, then it is hoped that a receptor-mediated capacitation pathway may provide several targets. Similarly, failures of capacitation contribute to infertility, which effects >10% of couples in the US, and new knowledge of the relevant pathways may lead to novel therapeutic strategies. PUBLICE HEALTH RELEVANCE: This project focuses on the control of sperm capacitation by pkdrej, a polycystin-1 family member. Capacitation is an obligatory event in the fertilization process and insight into the underlying mechanisms can help to control soaring population, which now exceeds 6,700 million world-wide, as well as provide novel treatments of infertility, which is estimated to affect 10-15% of couples in the US.