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Master of Science (M.S.)
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Despite the availability of a range of contraceptive methods, over 50% of pregnancies are unintended worldwide (~1,000,000/day). Male contraception remains an important area of research. Recent acceptability studies indicate that a high percentage of men would be willing to use a male contraceptive pill. Several non-hormonal targets for a male-based contraceptive pill have been brought to light recently including the testis-specific serine kinase (TSSK) family, which belongs to the AMPK kinase branch in the CAMK group. The finding that TSSK family members are postmeiotically expressed in male germ cells, together with the infertile phenotype found in both Tssk1/2 and Tssk6 mouse knock-out models, has led to the proposal that TSSKs play an important role in sperm function, making them excellent targets for drug design of novel male contraceptives. This research is aimed to the identification of potent, specific inhibitors for TSSK1 activity for the development of novel male contraceptive pills through the use of mice as an experimental model. Our hypothesis is that a single kinase inhibitor can specifically inhibit TSSK’s kinase activity without interfering with other sperm functions, or other tissue types. In this study, we have assessed the enzyme properties of vii recombinant human TSSK1 by application of a homogeneous, non-radioactive enzyme activity assay and mid-throughput screening of kinase inhibitors that block TSSK1 activity. Some of these inhibitors have proven to greatly reduce the activity of TSSK1 overall, but lack the specificity desired to be plausible for drug design. In parallel, our efforts are directed towards developing a functional in vivo assay using both CD1 and acrosin-GFP-transgenic mice (expressing Acr-GFP in the acrosome) based on our finding that TSSK1 is localized in the sperm acrosome, which points to a potential role of TSSKs in sperm acrosome reaction. The anticipated outcome of this research is to ultimately develop a reversible, non-hormonal male contraceptive. Our findings may also set the basis for studies on human sperm function towards a better understanding of male reproductive physiology and mechanisms of male infertility.
Majka, Julie, "In Vitro Screening for Small-Molecule Kinase Inhibitors of Testis-Specific Serine Kinase 1 (TSSK1), a Potential Target for Male Contraception" (2015). Masters Theses. 284.