Selecting sperm with distinct metabolic phenotypes to increase ART efficiency

选择具有不同代谢表型的精子以提高 ART 效率

• 批准号: 10608579
• 负责人: Christopher Bennett Geyer
• 金额: $ 45.08万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-19 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608579
• 关键词: Acrosome Reaction; Amino Acids; Assisted Reproductive Technology; Biochemical; Bioenergetics; Birth; Chemotaxis; Clinical; Competence; Computer Assisted; Couples; Coupling; DNA; DNA Damage; Data; Development; Embryo; Energy-Generating Resources; Environment; Exhibits; Exposure to; Family; Female; Fertilization; Fertilization in Vitro; Financial Hardship; Germ Cells; Glycolysis; Household; Human; Hyperactivity; In Vitro; Income; Intracytoplasmic Sperm Injections; Ions; Knowledge; Low income; Metabolic; Metabolism; Methods; Morphology; Mus; NADH; Natural Selections; Oxidation-Reduction; Oxidative Phosphorylation; Oxidoreductase; Pattern; Phenotype; Procedures; Process; Production; Respiration; Signal Transduction; Sperm Motility; Techniques; Testing; Tyrosine Phosphorylation; blastocyst; cell motility; cofactor; cost; experience; family burden; gain of function; in vitro testing; inhibitor; innovation; insight; loss of function; lower income families; metabolic phenotype; method development; novel; oocyte quality; oxidative damage; reproductive tract; response; sperm cell; sperm function; sperm quality; stem; success; sugar; trait

PROJECT SUMMARY/ABSTRACT More than 80,000 births in the US occur annually as a result of assisted reproductive technology (ART). The success of ART typically requires multiple expensive cycles that together exceed many US families’ yearly household incomes. The necessity of multiple ART cycles stems in part from an insufficient number of healthy preimplantation embryos. Healthy embryos are a direct product of the highest-quality gametes, yet limited methods exist to identify the highest-quality sperm. Within the female reproductive tract, sperm with the highest fertilization competence are naturally selected based on functional parameters – motility patterns, chemotaxis, and the acrosome reaction. The best fertilization-competent sperm also have the lowest levels of oxidative and DNA damage. Unfortunately, current clinical methods for selecting sperm for intracytoplasmic sperm injection (ICSI) do not leverage these parameters. The broad objective of this application is to define the biochemical mechanisms by which sperm undergo motility switching and fertilization competence, and results will both advance the state of basic knowledge and enable optimization of in vitro sperm selection techniques. The optimization of sperm selection for ART will in turn: 1) increase production of healthy embryos; 2) reduce average numbers of costly cycles; and thus 3) lessen the cost burden on lower-income families. In Aim 1, we will utilize complementary comprehensive bioenergetic phenotyping, computer assisted motility analysis (CASA), and a novel dehydrogenase screen to define the underlying mechanisms through which metabolites predictably modulate the essential motility patterns of mouse sperm. In Aim 2, we will test the hypothesis that predictable motility changes in response to metabolites can be used to select the best mouse sperm – those with normal morphology and low levels of DNA damage, the ability to navigate towards a chemotactic signal and initiate hyperactive motility, and complete the acrosome reaction. We will then employ in vitro fertilization (IVF) to determine whether mouse sperm selected based on these metabolism-based motility traits have enhanced ability to generate healthy embryos. In Aim 3, we will exploit our experience working with mouse sperm to define the fundamental differences in the metabolism-based motility responses of human sperm. This project is expected to identify the mechanisms connecting microenvironment to sperm function and thereby provide proof-of-concept for the rapid development of methods to optimize clinical selection of fertilization-competent human sperm for ART.

项目概要/摘要 在美国，每年有超过 80,000 名婴儿通过辅助生殖技术 (ART) 出生。 ART 的成功通常需要多个昂贵的周期，这些周期加起来超过了许多美国家庭每年的花费 家庭收入的多次 ART 周期的必要性部分源于健康人数不足。 植入前胚胎是最高质量配子的直接产物，但数量有限。 现有方法可以识别女性生殖道内质量最高的精子。 受精能力是根据功能参数自然选择的——运动模式、趋化性、 顶体反应最好的受精能力也具有最低的氧化和水平。 不幸的是，目前临床上选择精子进行胞浆内单精子注射的方法。 (ICSI) 不利用这些参数，该应用的主要目标是定义生化。 精子进行运动转换和受精能力的机制，结果将 基础知识的状态并能够优化体外精子选择技术。 优化 ART 的精子选择将依次：1) 增加健康胚胎的产量 2) 降低平均水平； 昂贵的周期数量；因此 3) 减轻低收入家庭的成本负担 在目标 1 中，我们将利用。 互补的综合生物能表型分析、计算机辅助运动分析 (CASA) 和 新型脱氢酶筛选，以确定代谢物可预测的潜在机制 调节小鼠精子的基本运动模式 在目标 2 中，我们将检验可预测的假设。 对代谢物的反应的运动变化可用于选择最好的小鼠精子——那些具有正常功能的精子 形态和低水平的 DNA 损伤，导航趋化信号并启动的能力 活动过度，并完成顶体反应，然后我们将采用体外受精（IVF）来完成。 确定根据这些基于代谢的运动特征选择的小鼠精子是否具有增强的能力 在目标 3 中，我们将利用我们在小鼠精子方面的经验来定义 该项目有望揭示人类精子基于新陈代谢的运动反应的根本差异。 确定微环境与精子功能之间的联系机制，从而提供概念验证 快速开发优化具有受精能力的人类精子临床选择的方法 艺术。