Grant: Operating Grant

Infertility is a common problem that is increasing, particularly in Western societies. Approximately 20-25% of infertility cases are due to the male partner and ~30% of additional cases are due to abnormalities in both partners. The causes of male infertility remain largely unknown. In order to fertilize eggs, sperm must undergo normal development and maturation. This involves the conversion of undifferentiated stem cells in the testis into mature elongated spermatids. These spermatids undergo further maturation in the epididymis and activation upon ejaculation into the female reproductive tract. Here the activated sperm acquire the necessary motility to move through the reproductive tract and then penetrate the outer layers of the egg structure to fuse with the egg. In order for proper development and maturation of spermatids to take place, proteins that are not required in the final sperm cells must be destroyed. My laboratory is studying the mechanisms by which the non-required proteins are degraded in developing spermatids. Defects in this breakdown of proteins may lead to abnormal development of sperm and infertility. Indeed we have recently observed that mice lacking USP2, an enzyme in this pathway of protein breakdown, are almost completely infertile. Their sperm have defects in motility and in ability to penetrate the coatings around the egg. Therefore, we will compare the sperm from mice lacking USP2 with normal sperm to determine the cellular and molecular mechanisms for these abnormalities. Defects in sperm motility are found in the majority of infertile men and so this research may lead to new approaches to treating infertility or new contraceptive methods in men. Indeed, we will begin exploring in this project whether there are abnormalities of the USP2 gene in infertile men.