Altered metabolism in embryo generated by in vitro fertilization

体外受精产生的胚胎代谢发生改变

• 批准号: 10583414
• 负责人: PAOLO RINAUDO
• 金额: $ 54.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583414
• 关键词: Adult; Adult Children; Affect; Amino Acids; Assisted Reproductive Technology; Beta Cell; Bioethics; Biological Markers; Cells; Child; Chromatin; Clinical; Closure by clamp; Conceptions; Congresses; Cues; Data; Data Set; Defect; Development; Diabetes Mellitus; Disease; Embryo; Embryonic Induction; Energy-Generating Resources; Environment; Environmental Risk Factor; Enzymes; Epigenetic Process; Exhibits; Fertilization in Vitro; Fetus; Functional disorder; Gene Expression; Gene Expression Profile; Genome; Germ Cells; Glucose; Glucose Intolerance; Glycolysis; Goals; Growth; Growth and Development function; HIF1A gene; Health; Histones; Homeostasis; Human; Hyperglycemia; Hypertension; Impairment; In Vitro; Incidence; Infertility; Infusion procedures; Life; Link; Metabolic; Metabolic Pathway; Metabolism; Mission; Mitochondria; Modeling; Molecular; Mus; National Institute of Child Health and Human Development; Obesity; Organism; Outcome; Oxygen; Pathway interactions; Patients; Phenotype; Physiology; Placenta; Placentation; Play; Prediabetes syndrome; Procedures; Process; Reactive Oxygen Species; Research; Risk; Role; Secondary to; Shapes; Signal Transduction; Signaling Molecule; Site; Source; Stress; Technology; Tissues; United States National Institutes of Health; Waste Products; Work; adverse outcome; blastocyst; blood glucose regulation; career; clinically relevant; critical period; disorder risk; extracellular; fetal; improved; in vivo; infertility treatment; metabolic phenotype; novel; offspring; oxidative damage; postnatal; programs; protein expression; stable isotope; theories; trend

Project Summary/Abstract We propose studies to evaluate the direct impact of preimplantation embryo manipulation on the metabolism of embryos and tissues. Because embryo manipulation is routinely used in the context of Assisted Reproductive Technologies (ART) to treat patients with infertility, these goals have wide clinical implications. In fact, more than 8 million children have been conceived by the technologies and more than 2.5 million in vitro fertilization (IVF) cycles occur every year. Hence, there is great need to know if preimplantation embryo manipulation induces subtle, but possibly long-lasting effects on the health of ART offspring. The focus of this application is at the core of the PI’s expertise, as he has devoted most of his career to understanding how ex-vivo embryo manipulation is associated with changes in the embryo (altered gene expression, development, mitochondria function) and long-term maladaptive changes in the offspring (defects in placentation, altered postnatal growth and ultimately altered glucose homeostasis). While these results are important, multiple key questions remain unanswered. In particular, the molecular mechanisms responsible to alter growth and metabolism in adults are unknown. For example, it is unclear if metabolism is altered in embryos generated in vitro and if these metabolic alterations are maintained in adults and responsible to cause abnormal glucose handling in adults generated by IVF. Importantly, the President's Council on Bioethics and Congress urged the NICHD to determine whether these adverse outcomes are specifically related to ART procedures. Exciting novel preliminary data suggest that alteration of glycolysis and lactate metabolism are present in embryos and possibly in adult generated by IVF. Based on preliminary data, objectives of this application are to: 1) understand if alteration of glycolytic pathways exist in embryo who have undergone different degrees of manipulation; discover the mechanisms leading to 2) metabolic alterations and 3) if specific epigenetic changes exist; finally, 4) study if these alterations are maintained in adult mice conceived by IVF. Our central hypothesis is that the ex vivo embryonic environment, deviating profoundly from the in vivo conditions (different oxygen concentrations, altered energetic sources) cause increase in reactive oxygen species. Reparative mechanisms will induce metabolic alterations and epigenetic changes. These molecular alterations will be maintained in adult offspring resulting in altered glucose and lactate metabolism. Regarding expected outcomes, we will: 1) determine what culture conditions produce greater or smaller change in glycolysis in embryos, 2) discover the pathways responsible for these changes, 3) describe the specific epigenetic changes induced by these alterations and finally 4) discover what metabolic pathways are altered in IVF offspring. These datasets are expected to have an important impact because of the translational value to the fields of developmental reprogramming, diabetes, obesity and for patients affected with infertility.

项目摘要/摘要 我们提出的研究旨在评估植入前胚胎操纵对代谢的直接影响 胚胎和组织。因为胚胎操纵通常是在辅助生殖的背景下使用的 技术（ART）治疗不孕症患者，这些目标具有广泛的临床意义。实际上，更多 这些技术已经构思了800万儿童，体外受精超过250万 （IVF）每年发生周期。因此，非常需要知道植入前胚胎是否操纵 引起微妙但可能对艺术后代健康的长期影响。 该应用程序的重点是PI专业知识的核心，因为他的职业生涯大部分时间都致力于 了解外部胚胎操纵如何与胚胎变化相关（基因改变） 表达，发育，线粒体功能）和后代的长期适应不良变化（缺陷 在安置中，产后生长改变，最终改变了葡萄糖稳态）。 尽管这些结果很重要，但多个关键问题仍未解决。特别是分子 负责改变成人生长和代谢的机制尚不清楚。例如，目前尚不清楚是否 代谢在体外产生的胚胎中发生了改变，如果这些代谢改变在成年人中保持 并负责在IVF产生的成年人中引起异常葡萄糖处理。重要的是，总统的 生物伦理学和国会委员会敦促NICHD确定这些不利结果是否是 与艺术程序特别相关。 令人兴奋的新型初步数据表明，糖酵解和裂解代谢的改变存在于 胚胎，可能是由IVF产生的成年人。基于初步数据，此应用程序的目标是 至：1）了解经历了不同程度的胚胎中是否存在糖酵解途径的改变 操纵；发现导致2）代谢改变的机制，3）如果特定表观遗传 存在变化；最后，4）研究是否在IVF构想的成年小鼠中保持这些改变。我们的中心 假设是，离体胚胎环境与体内条件深远（不同） 氧浓度，能量来源改变）导致活性氧的增加。修复 机制将诱导代谢改变和表观遗传变化。这些分子改变将是 在成年后代维持，导致葡萄糖改变和新陈代谢。关于预期 结果，我们将：1）确定哪些培养条件在糖酵解中会产生更大或更小的变化 胚胎，2）发现负责这些变化的途径，3）描述特定的表观遗传变化 由这些变化引起的，最后4）发现IVF后代改变了哪些代谢途径。 由于对字段的翻译价值，预计这些数据集将产生重要的影响 发育重编程，糖尿病，肥胖症以及患有不育症影响的患者。