Phosphoinositide signaling and sperm fertility

磷酸肌醇信号传导和精子生育能力

• 批准号: 7990481
• 负责人: Harvey M Florman
• 金额: $ 8.23万
• 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/7990481
• 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 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）：哺乳动物精子以不动且不育的状态储存在雄性生殖道中。到达受精部位并成功与卵子相互作用的能力只有在雌性生殖道内孵化期间才能形成。精子中导致这种功能成熟的分子变化统称为获能。这些过程对于繁殖至关重要。因此，获能的生理调节因子可能为避孕干预提供新的靶点。 精子膜中的多磷酸化磷酸肌醇介导获能和精卵相互作用的关键步骤。然而，人们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，我们重点关注 3'-磷酸肌醇磷酸酶 Tpte。正如将要讨论的，Tpte 转录物仅在生精细胞中检测到，并且预期的酶活性表明其在获能中发挥作用。此外，初步数据表明，小鼠附睾尾部精子的前头和鞭毛中含有具有酶活性的 Tpte 蛋白。然而，由于缺乏试剂，我们没有关于这种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 Tpte 基因座突变且缺乏磷酸酶活性的小鼠品系，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。这项探索性研究代表了确定 Tpte 以及其他磷酸肌醇激酶和磷酸酶在精子功能和生殖中的作用的长期努力的第一阶段。 公共健康相关性：该项目的重点是控制精子的生育能力。因此，它直接涉及两个与健康相关的问题。首先，不孕不育症影响了美国 10-15% 的夫妇，这项工作可能会带来针对这种情况的新治疗方法。其次，目前全球人口估计超过 67 亿。该项目研究了一种精子特异性脂质磷酸酶，它将为避孕干预提供新的靶点。这里进行的实验将确定这种磷酸酶在精子生育力中的作用，并开始表征磷酸酶活性。