Discovery and Characterization of an Endogenous Inhibitor of Soluble Adenylyl Cyclase

获得避孕药具和了解不孕症的机制是健全生殖健康的关键方面。不幸的是，现有的避孕方法并不适合或方便于每个人，而且男性的选择严重有限。此外，虽然不孕症被认为是一种会带来许多负面后果的残疾，但人们对它的了解并不充分；据估计，50%的男性不育病例病因不明。阐明精子的功能和更好地了解精子生物学可能会对这些领域有所启发。可溶性腺苷酸环化酶（sAC, ADCY10）对精子功能和受精至关重要。我发现了一种以前未被认识到的调节sAC活性的机制；一种内源性sAC小分子抑制剂。在本课题中，我将通过检测内源性抑制剂在体细胞组织和雄性配子中的分布，对内源性抑制剂进行分子鉴定，确定其抑制sAC的机制，并探讨其生理意义。这些研究提出确定第一个已知的降低sAC活性的生理调节因子，这将扩大我们对sAC的认识。更好地了解内源性抑制剂可以为开发非激素男性避孕药提供潜在的先导化合物，并确定其水平是否发生病理生理变化可能揭示不孕症的新机制。

Access to contraceptives and understanding mechanisms of infertility are key aspects of robust reproductive health. Unfortunately, existing contraceptive methods are not suitable or convenient for everyone, and the options for men are severely limited. In addition, while infertility is recognized as a disability carrying many negative consequences, it is not well understood; it is estimated that 50% of male infertility cases have an unknown etiology. Elucidating sperm functions and gaining a better understanding of sperm biology may shed light on these areas. Soluble adenylyl cyclase (sAC, ADCY10) is essential for sperm function and fertilization. I have uncovered the existence of a previously unappreciated mechanism for regulating sAC activity; an endogenous small molecule inhibitor of sAC. In this proposal, I will molecularly identify the endogenous inhibitor, determine its mechanism of inhibiting sAC, and explore its physiological significance by examining the distribution of the endogenous inhibitor in somatic tissues and male gametes. These studies propose to identify the first known physiological regulator that decreases sAC activity which will expand our knowledge of sAC. Gaining a better understanding of the endogenous inhibitor could provide a potential lead compound for the development of a non-hormonal male contraceptive and determining whether its levels change pathophysiologically may reveal new mechanisms of infertility.