Phosphoinositide signaling and sperm fertility

磷酸肌醇信号传导和精子生育能力

• 批准号: 8121568
• 负责人: Harvey M Florman
• 金额: $ 7.9万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-05 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121568
• 关键词: 1-Phosphatidylinositol 4-Kinase; Accounting; Acrosome Reaction; Address; Affect; Anterior; Biochemical; Biological Models; Contraceptive Agents; Couples; Data; Development; Environment; Female; Fertility; Fertilization; Fertilization failure; Flagella; Genes; Genetic Models; Head; Health; Human; In Vitro; Infertility; Interruption; Intervention; Lead; Link; Lipids; Mediating; Membrane; Membrane Potentials; Modeling; Molecular; Mus; Mutate; NP protein; Orthologous Gene; Pattern; Phenotype; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Population; Process; Property; Proteins; Reagent; Regulation; Reproduction; Role; Signal Pathway; Signal Transduction; Site; Sperm Maturation; Sperm-Ovum Interactions; Spermatogenic Cell; Staging; Substrate Specificity; Transcript; Transducers; Work; Zona Pellucida; cell motility; contraceptive target; egg; in vivo; information model; information processing; male; novel; protein function; public health relevance; reproductive; research study; sperm cell; sperm function; tensin

DESCRIPTION (provided by applicant): Mammalian sperm are stored in the male reproductive tract in an immotile and infertile state. The ability to reach the site of fertilization and to interact with eggs successfully is only developed during incubation within the female reproductive tract. The molecular alterations in sperm that account for this functional maturation are, collectively, known as capacitation. These processes are essential for reproduction. As such, the physiological regulators of capacitation may provide novel targets for contraceptive intervention. Polyphosphorylated phosphoinositides in the sperm membrane mediate key steps in capacitation and sperm-egg interaction. However, little is known about the lipid kinases and phosphatases that regulate the levels of these phosphoinositides. Here, we focus on the 3'-phosphoinositide phosphatase, Tpte. As will be discussed, Tpte transcripts are detected only in spermatogenic cells and the anticipated enzymatic activity suggests a role in capacitation. In addition, preliminary data is presented showing that cauda epididymal mouse sperm contain enzymatically-active Tpte protein in the anterior head and in the flagellum. However, we have no direct information regarding the role of this protein in sperm due to a lack of reagents. In this exploratory study we will generate a mouse line in which the Tpte locus is mutated and lacking phosphatase activity, and examine the reproductive phenotype of these mice. In addition we will begin an analysis of the catalytic activity of Tpte phosphatase activity. This exploratory study represents the first stage of a long-term effort to determine the role of Tpte, as well as other phosphoinositide kinases and phosphatases, in sperm function and reproduction. PUBLIC HEALTH RELEVANCE: This project focuses on the control of sperm fertility. As such, it directly relates to two issues of health relevance. First, episodes of infertility affect 10-15% of couples in the US and this work may lead to new treatments for this condition. Second, population is now estimated to exceed 6,700 million world-wide. This project examines a sperm-specific lipid phosphatase that would provide a novel target for contraceptive intervention. The experiments carried out here will determine the role of this phosphatase in sperm fertility and begin characterization of phosphatase activity.

描述（由申请人提供）：哺乳动物的精子存储在雄性生殖道中，处于不可或缺状态。只有在女性生殖道中孵育期间才能发展出施肥部位并成功与卵相互作用的能力。考虑到这种功能成熟的精子中的分子改变，被称为电容。这些过程对于繁殖至关重要。因此，电容的生理调节剂可以为避孕干预提供新的目标。 精子膜中的多磷酸化磷酸肌醇介导了电容和精子 - 蛋的相互作用的关键步骤。但是，对调节这些磷酸肌醇水平的脂质激酶和磷酸酶知之甚少。在这里，我们专注于3'-磷酸肌醇磷酸酶Tpte。正如将要讨论的那样，仅在生精细胞中检测到TPTE转录本，预期的酶促活性表明在电容中起作用。此外，还提供了初步数据，表明Cauda附睾小鼠精子在前头和鞭毛中含有酶活性的TPTE蛋白。但是，由于缺乏试剂，我们没有有关该蛋白质在精子中的作用的直接信息。在这项探索性研究中，我们将生成一条小鼠系，其中TPTE基因座被突变并缺乏磷酸酶活性，并检查这些小鼠的生殖表型。此外，我们将开始分析TPTE磷酸酶活性的催化活性。这项探索性研究是确定TPTE以及其他磷酸肌醇激酶和磷酸酶在精子功能和繁殖中的作用的长期努力的第一阶段。 公共卫生相关性：该项目侧重于控制精子生育能力。因此，它直接与健康相关性问题有关。首先，不育的发作影响美国10-15％的夫妇，这项工作可能会导致这种情况的新治疗方法。其次，估计全球范围内的人口估计超过67亿。该项目研究了一种精子特异性脂质磷酸酶，该脂质磷酸酶将为避孕干预提供新的靶标。这里进行的实验将确定该磷酸酶在精子生育中的作用，并开始表征磷酸酶活性。