Cyclic AMP Action During Sperm Function

精子功能期间的循环 AMP 作用

• 批准号: 7370822
• 负责人: George L. Gerton
• 金额: $ 33.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-04 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370822
• 关键词: Abbreviations; Ablation; Acrosome Reaction; Address; Adenylate Cyclase; Animals; Artificial Insemination; Assisted Reproductive Technology; Catalytic Domain; Cells; Clear Cell; Competence; Condition; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Environment; Epididymis; Epithelium; Event; Family; Fertilization; Fertilization in Vitro; Genes; Genetic; Genotype; Germ Cells; Glucocorticoids; Glycogen Synthase Kinase 3; Goals; Guanine; Guanine Nucleotide Exchange Factors; Hydrochloride Salt; In Vitro; Infertility; Intracytoplasmic Sperm Injections; Light; Localized; Male Infertility; Mass Spectrum Analysis; Membrane; Methodology; Molecular; Mus; PDPK1 gene; Pathway interactions; Pattern; Phenotype; Phosphatidylinositols; Phosphotransferases; Process; Protein Analysis; Protein Kinase; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Public Health; RAC-Alpha Serine/Threonine Kinase; Research; Role; Second Messenger Systems; Serum; Signal Pathway; Signal Transduction; Source; Sperm Capacitation; Sperm Maturation; Sperm Motility; Spermatogenesis; Testing; Testis; Thinking; Transplantation; Two-Dimensional Polyacrylamide Gel Electrophoresis; Tyrosine Phosphorylation; analog; base; calcium bicarbonate; cell motility; clinically significant; contraceptive target; homologous recombination; improved; male; mutant; novel; oxidation; phosphoric diester hydrolase; response; second messenger; sperm cell; sperm function; sperm protein; tris(2-carboxyethyl)phosphine; zygote

DESCRIPTION (provided by applicant): The second messenger cyclic AMP (cAMP) regulates a broad spectrum of cellular activities. It is critical for mammalian spermatogenesis, maturation of sperm in the epididymis, and capacitation, the post-epididymal maturational process that sperm undergo prior to fertilization. The bicarbonate- and calcium-responsive `soluble' adenylyl cyclase (SACY) is the predominant source of cAMP in both mouse germ cells and sperm. When the Sacy gene is ablated by homologous recombination, the result is male infertility. Although spermatogenesis in the testis appears to proceed undisturbed, the morphologically normal sperm are immotile. Motility can be partially rescued with membrane permeable cAMP analogs, highlighting the importance of cAMP in this process. However, these sperm are not able to fertilize eggs in vitro, indicating that the sperm are still defective. To address our long-term goal of understanding the role of cAMP and its signaling pathways in promoting fertilization-competence of mammalian sperm, we will: 1) establish whether the Sacy-null phenotype is the result of events occurring during spermatogenesis and/or the course of epididymal maturation using reciprocal spermatogonial transplantation; 2) examine the molecular bases for the flagellar angulation and immotility seen in Sacy-null sperm by identifying protein differences in the sperm of the two genotypes, and, 3) determine the role that EPACs, a family of cAMP-activated proteins, have on sperm motility. The fact that fertilization does not occur without proper sperm maturation in the epididymis and sperm capacitation emphasizes the clinical significance of this project. Although this block to fertilization can be circumvented by assisted reproductive technologies such as intracytoplasmic sperm injection, the findings from the research detailed in this application may allow the clinician to modify in vitro fertilization and artificial insemination methodologies to enhance capacitation. These studies may identify new pathways and targets for contraceptive development. Project Narrative: The relevance of this project to public health is that if sperm do not 'capacitate', they can not fertilize an egg. Understanding the role of SACY during spermatogenesis in the testis, sperm maturation in the epididymis, and sperm capacitation will allow us to improve the efficacy of sperm becoming fertilization-competent.

描述(申请人提供)：第二信使环磷酸腺苷(CAMP)调节广泛的细胞活动。它对哺乳动物的精子发生、精子在附睾中的成熟以及获能(精子受精前经历的附睾期后成熟过程)都是至关重要的。小鼠生殖细胞和精子中cAMP的主要来源是对碳酸氢盐和钙有反应的“可溶性”腺苷环化酶(Sacy)。当Sacy基因通过同源重组被去除时，结果是男性不育。虽然精子在睾丸中的发生似乎没有受到干扰，但形态正常的精子是静止的。膜通透性cAMP类似物可以部分挽救运动，强调cAMP在这一过程中的重要性。然而，这些精子无法在体外使卵子受精，这表明这些精子仍然是有缺陷的。为了解决我们了解cAMP及其信号通路在促进哺乳动物精子受精能力方面的作用的长期目标，我们将：1)确定Sacy零表型是否是精子发生过程中和/或附睾成熟过程中发生的事件的结果，使用相互的精原移植；2)通过鉴定两种基因型精子中的蛋白质差异，研究Sacy零精子中鞭毛成角和静止的分子基础；以及3)确定EPACs(一组cAMP激活蛋白家族)对精子活力的作用。事实上，如果精子在附睾处没有适当的成熟和精子获能，受精是不会发生的，这一事实强调了这个项目的临床意义。尽管卵胞浆内单精子注射等辅助生殖技术可以绕过受精的障碍，但本申请中详细介绍的研究结果可能允许临床医生修改体外受精和人工授精方法，以提高获能能力。这些研究可能为避孕开发确定新的途径和目标。项目简介：该项目与公共卫生的相关性在于，如果精子不能‘获能’，它们就不能使卵子受精。了解Sacy在睾丸精子发生、附睾精子成熟和精子获能过程中的作用，将有助于我们提高精子受精能力的效率。