Discovery and Characterization of an Endogenous Inhibitor of Soluble Adenylyl Cyclase

可溶性腺苷酸环化酶内源性抑制剂的发现和表征

• 批准号: 10643975
• 负责人: Jacob Ferreira
• 金额: $ 4.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10643975
• 关键词: Adenosine Triphosphate; Adenylate Cyclase; Affinity; Anions; Area; Binding Sites; Biology; Chromatography; Circular Dichroism; Contraceptive Agents; Contraceptive methods; Crystallization; Cyclic AMP; Cyclization; Cytosol; Data; Development; Endogenous Factors; Enzymes; Epididymis; Etiology; Family Planning; Female; Fertility; Fertilization; Germ Cells; High Pressure Liquid Chromatography; Human; In Vitro; Individual; Infertility; Investigation; Kinetics; Knowledge; Laboratories; Lead; Letters; Liver; Male Contraceptive Agents; Male Infertility; Mammals; Mass Spectrum Analysis; Measures; Mediating; Membrane; Methanol; Methods; Modality; Molecular; Morphology; Mus; Nuclear Magnetic Resonance; Oocytes; Particulate; Pathologic; Patients; Physiological; Precipitation; Process; Property; Proteins; Recombinants; Regulation; Reproductive Health; Research Contracts; Role; Sperm Capacitation; Structure; Testing; Testis; Time; Tissues; Work; adenylyl cyclase 2; cell motility; disability; improved; inhibitor; male; men; novel; novel therapeutics; pharmacologic; reproductive; response; reversed phase chromatography; small molecule; small molecule inhibitor; sperm cell; sperm function

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.

获得避孕药具和了解不孕机制是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每个人，男性的选择严重有限。此外，尽管不育被认为是一种具有许多负面后果的残疾，但人们对其了解不深；据估计，50%的男性不育病例的病因不明。阐明精子的功能，更好地了解精子生物学，可能会对这些领域有所帮助。可溶性腺酰环化酶(SAC，ADCY10)是精子功能和受精所必需的。我发现了一种以前未被认可的调节SAC活性的机制：一种SAC的内源性小分子抑制物。在本方案中，我将从分子水平上鉴定内源抑制物，确定其抑制SAC的机制，并通过检测内源抑制物在体细胞组织和雄配子中的分布来探讨其生理意义。这些研究建议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的了解。更好地了解内源性抑制物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，可能揭示不育的新机制。