SLO3 KO MOUSE: A TOOL TO REVEAL VOLTAGE-DEPENDENT PROCESSES IN SPERM FERTILITY

SLO3 KO 小鼠：揭示精子受精过程中电压依赖性过程的工具

• 批准号: 10152638
• 负责人: Celia M Santi
• 金额: $ 32.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-02 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152638
• 关键词: Acrosome Reaction; Affect; Binding; Calcium; CatSper; Cell membrane; Cells; Charge; Clinical; Couples; Data; Diagnosis; Electrophysiology (science); Event; Fertility; Fertilization; Fertilization failure; Fertilization in Vitro; Functional disorder; Goals; Human; Imaging Techniques; Impairment; Infertility; Ion Channel; Ions; Knock-out; Knockout Mice; Laboratories; Male Contraceptive Agents; Male Infertility; Measurement; Measures; Mediating; Membrane; Membrane Potentials; Molecular; Morphology; Mus; Mutation; Oocytes; Permeability; Play; Potassium; Potassium Channel; Process; Public Health; Publishing; Regulation; Reporting; Rest; Role; Sampling; Seminal fluid; Sperm Capacitation; Sperm Count Procedure; Testing; Work; cell motility; exome sequencing; idiopathic infertility; improved; male; male fertility; men; novel diagnostics; sperm cell; sperm function; therapeutic target; tool; voltage; voltage sensitive dye; zygote

PROJECT SUMMARY Infertility affects 10% to 15% of couples worldwide, and a male factor contributes to around 50% of these cases. Male infertility is diagnosed predominantly on the results of standard semen analysis, which provides information about sperm count, morphology, and motility. However, many sperm samples from infertile men pass this standard analysis but, for unknown reasons, still lack the ability to fertilize an egg. Thus, to improve male fertility, our long-term goal is to reveal the basic mechanisms by which sperm become competent to fertilize an egg and to identify new diagnostic strategies and therapeutic targets. In many mammalian species membrane hyperpolarization (when the intracellular voltage becomes more negative) is a key event in sperm becoming competent to fertilize an egg (capacitation). We previously showed that sperm from mice that lack the sperm-specific SLO3 K+ channels cannot undergo membrane hyperpolarization and are infertile. Hyperpolarization is also associated with human sperm capacitation, and a depolarized membrane is associated with impaired fertilization capacity in human sperm. However, the ion channels responsible for regulating membrane potential in human sperm are uncertain. In this proposal we aim to determine the ion permeabilities that underlie membrane potential changes in human sperm and how membrane hyperpolarization regulates changes in intracellular calcium (another key aspect of sperm capacitation). We propose that human sperm membrane potential is regulated by the potassium (K+) channel SLO3 as in mouse sperm and that SLO3 dysfunction might be responsible for some cases of male idiopathic infertility. These studies might also produce a valuable clinical tool – measurement of sperm membrane potential using voltage sensitive dyes - to predict human sperm fertilization capacity. Additionally, if SLO3 plays an essential role in human fertilization in humans as it does in mice, this sperm-specific channel would provide a new, non-hormonal target for a male contraceptive.

项目概要 全球 10% 至 15% 的夫妇患有不孕症，其中约 50% 是由男性因素造成的 男性不育症的诊断主要依靠标准精液分析的结果。 提供有关精子数量、形态和活力的信息。然而，许多精子样本来自。 不育男性通过了这一标准分析，但由于未知原因，仍然缺乏使卵子受精的能力。 因此，为了提高男性生育能力，我们的长期目标是揭示精子的基本机制 具有使卵子受精并确定新的诊断策略和治疗靶点的能力。 在许多哺乳动物物种中，膜超极化（当细胞内电压变得更大时） 阴性）是精子有能力使卵子受精（获能）的关键事件。 研究表明，缺乏精子特异性 SLO3 K+ 通道的小鼠的精子无法进入膜 超极化和不育 超极化也与人类精子获能有关。 去极化膜与人类精子的受精能力受损有关。 负责调节人类精子膜电位的离子通道尚不确定。 我们的提案旨在确定人类膜电位变化背后的离子渗透性 精子以及膜超极化如何调节细胞内钙的变化（另一个关键 我们认为人类精子膜电位受 小鼠精子中的钾 (K+) 通道 SLO3，SLO3 功能障碍可能是导致 这些研究也可能产生一个有价值的临床工具—— 使用电压敏感染料测量精子膜电位 - 预测人类精子 此外，SLO3 在人类受精过程中发挥着重要作用。 在小鼠身上，这种精子特异性通道将为雄性提供一个新的非激素目标 避孕药。