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

基本信息

批准号：
10456053
负责人：
Jacob Ferreira
金额：
$ 4.68万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
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/10456053
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 Fertility Fertilization Germ Cells High Pressure Liquid Chromatography Human In Vitro Individual Infertility Investigation Kinetics Knowledge Laboratories Lead Letters Light Liver Male Contraceptive Agents Male Infertility Mammals Mass Spectrum Analysis Measures Mediating Methanol Methods Modality Molecular Morphology Mus Nuclear Magnetic Resonance Oocytes Particulate Pathologic Patients Pharmacology 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 reproductive response reversed phase chromatography small molecule small molecule inhibitor sperm cell sperm function

项目摘要

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不育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适合所有人，男性的选择也受到严重限制。此外，虽然不孕不育被认为是一种会带来许多负面后果的残疾，但人们对其了解还不够深入。据估计，50%的男性不育病例病因不明。阐明精子的功能并更好地了解精子生物学可能会为这些领域带来启发。可溶性腺苷酸环化酶（sAC、ADCY10）对于精子功能和受精至关重要。我发现了一种以前未被重视的调节 sAC 活动的机制的存在； sAC 的内源性小分子抑制剂。在本提案中，我将从分子角度鉴定内源性抑制剂，确定其抑制sAC的机制，并通过检查内源性抑制剂在体细胞组织和雄配子中的分布来探索其生理意义。这些研究旨在确定第一个已知的降低 sAC 活性的生理调节剂，这将扩大我们对 sAC 的了解。更好地了解内源性抑制剂可以为非激素男性避孕药的开发提供潜在的先导化合物，并确定其水平是否发生病理生理学变化可能揭示不育的新机制。