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.

项目摘要/摘要 由于辅助生殖技术（ART），美国每年有80,000多个出生。这 艺术的成功通常需要多个昂贵的周期，这些周期共同超过许多美国家庭的年度 家庭收入。多个艺术周期的必要条件部分是由于不足数量的健康 植入前胚胎。健康的胚胎是最高质量游戏的直接产物，但有限 存在识别最高质量精子的方法。在女性复制道中，精子最高 根据功能参数 - 运动模式，趋化性，趋化性，自然选择受精能力 和高级反应。最好的受精的精子也具有最低水平的氧化和 DNA损伤。不幸的是，当前选择精子注射精子的临床方法 （ICSI）不要利用这些参数。该应用的广泛目的是定义生化 精子经历运动转换和受精能力的机制，结果既将 推进基本知识的状态并能够优化体外精子选择技术。这 对艺术的精子选择的优化反过来：1）增加健康胚胎的产生； 2）降低平均水平 昂贵的周期数； 3）减少伯恩在低收入家庭上的成本。在AIM 1中，我们将使用 完全全面的生物能表型，计算机辅助运动分析（CASA）和A 新型脱氢酶筛选以定义可以预见的代谢物的潜在机制 调节小鼠精子的基本运动模式。在AIM 2中，我们将检验可预测的假设 响应代谢物的运动变化可用于选择最佳的鼠标精子 - 那些正常的精子 形态学和低水平的DNA损伤，通向趋化信号并启动的能力 多动运动，并完成跨反应。然后，我们将在体外受精（IVF）中 确定基于这些基于新陈代谢的运动特征选择的小鼠精子是否具有增强的能力 产生健康的胚胎。在AIM 3中，我们将探索与鼠标精子一起工作以定义的经验 人类精子基于代谢的运动反应的基本差异。期望这个项目 确定将微环境连接到精子功能的机制，从而提供概念验证 为了快速开发方法，以优化临床选择施肥能力的人类精子 艺术。