Cyclic AMP Action During Sperm Function

精子功能期间的循环 AMP 作用

• 批准号: 8049415
• 负责人: George L. Gerton
• 金额: $ 1.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049415
• 关键词: Abbreviations; Ablation; Acrosome Reaction; Address; Adenylate Cyclase; Animals; Artificial Insemination; Assisted Reproductive Technology; Catalytic Domain; Cells; Clear Cell; Competence; 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; 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; Research; Role; Second Messenger Systems; Serum; Signal Pathway; Signal Transduction; Source; Sperm Capacitation; Sperm Maturation; Sperm Motility; Spermatogenesis; Testing; Testis; 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. 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（由申请人提供）：第二信使循环AMP（CAMP）调节了广泛的细胞活性。这对于哺乳动物的精子发生，附睾精子的成熟以及电容，这是精子在受精之前经历的术后成熟过程。碳酸氢盐和钙响应的“可溶性”腺苷酸环化酶（SACY）是小鼠生殖细胞和精子中cAMP的主​​要来源。当Sacy基因通过同源重组消融时，结果是男性不育症。尽管睾丸中的精子发生似乎不受干扰，但形态上正常的精子是不受干扰的。可以通过膜可渗透的营地类似物来部分救出运动，从而强调了在此过程中训练营的重要性。但是，这些精子无法在体外施肥，表明精子仍然有缺陷。为了解决我们的长期目标，即了解CAMP及其信号通路在促进哺乳动物精子的施肥能力方面的作用，我们将：1）确定Sacy-null表型是否是使用恋爱精子成熟过程中精子发生过程中发生的事件的结果； 2）通过鉴定两种基因型的精子中的蛋白质差异，研究了在Sacy-Null精子中观察到的鞭毛角度和不动力的分子底部，以及3）确定在cAMP激活的蛋白质家族中具有对精子运动的作用。如果没有适当的精子成熟，则无法在附睾和精子电容中进行施肥，这一事实强调了该项目的临床意义。尽管可以通过辅助生殖技术（例如胞质精子注射）来规避这种施肥的障碍，但本应用中详细介绍的研究的发现可能使临床医生可以修改体外受精和人工授精的方法，以增强能力。这些研究可能会确定避孕开发的新途径和目标。项目叙述：该项目与公共卫生的相关性是，如果精子不“能力”，它们就无法施肥。了解Sacy在睾丸中的精子发生过程中的作用，附睾中的精子成熟以及精子能力将使我们能够提高精子的功效，使其具有受精的能力。项目叙述 该项目与公共卫生的相关性是，如果精子不“能力”，它们就无法施肥。 了解Sacy在睾丸中精子发生中的作用，附睾的精子成熟和 精子电容将使我们能够提高精子能够受精的能力。