Cyclic AMP Action During Sperm Function

精子功能期间的循环 AMP 作用

基本信息

批准号：
8206606
负责人：
George L. Gerton
金额：
$ 32.13万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-04 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8206606
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

项目摘要

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）：第二信使环磷酸腺苷（cAMP）调节广泛的细胞活性。它对于哺乳动物的精子发生、附睾中精子的成熟以及获能（精子在受精前经历的附睾后成熟过程）至关重要。碳酸氢盐和钙响应性“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基因被同源重组消除时，结果就是男性不育。尽管睾丸中的精子发生似乎不受干扰，但形态正常的精子是不动的。膜渗透性 cAMP 类似物可以部分挽救运动能力，这凸显了 cAMP 在此过程中的重要性。然而，这些精子无法在体外使卵子受精，这表明精子仍然有缺陷。为了实现我们了解 cAMP 及其信号通路在促进哺乳动物精子受精能力中的作用的长期目标，我们将：1）确定 Sacy 无效表型是否是精子发生过程中发生的事件的结果和/或使用相互精原细胞移植实现附睾成熟的过程； 2) 通过识别两种基因型精子中的蛋白质差异，检查 Sacy 无效精子中鞭毛角度和不动的分子基础，并且 3) 确定 EPAC（cAMP 激活蛋白家族）在精子活力。如果附睾中的精子没有适当成熟并且精子获能，受精就不会发生，这一事实强调了该项目的临床意义。尽管这种受精障碍可以通过辅助生殖技术（例如胞浆内单精子注射）来规避，但本申请中详细研究的结果可能允许临床医生修改体外受精和人工授精方法以增强获能。这些研究可能会确定避孕药具开发的新途径和目标。项目叙述：该项目与公共健康的相关性在于，如果精子不能“获得能力”，它们就无法使卵子受精。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使我们能够提高精子具有受精能力的效率。项目叙述该项目与公共健康的相关性在于，如果精子不能“获得能力”，它们就无法使卵子受精。了解 SACY 在睾丸精子发生、附睾精子成熟过程中的作用，以及精子获能将使我们能够提高精子受精能力的效率。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Heads or tails? Structural events and molecular mechanisms that promote mammalian sperm acrosomal exocytosis and motility.

DOI：
10.1002/mrd.21393
发表时间：
2012-01
期刊：
MOLECULAR REPRODUCTION AND DEVELOPMENT
影响因子：
2.5
作者：
Buffone, Mariano G.;Ijiri, Takashi W.;Cao, Wenlei;Merdiushev, Tanya;Aghajanian, Haig K.;Gerton, George L.
通讯作者：
Gerton, George L.

Transitional states of acrosomal exocytosis and proteolytic processing of the acrosomal matrix in guinea pig sperm.