Insights into fetal brain and placental metabolism using high-resolution magic angle spinning magnetic resonance spectroscopy

使用高分辨率魔角旋转磁共振波谱深入了解胎儿大脑和胎盘代谢

• 批准号: RGPIN-2020-06694
• 负责人: Cahill, Lindsay
• 金额: $ 1.75万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=741264
• 关键词: Insights; into; fetal; brain; placental

During pregnancy, appropriate placental metabolism is essential for fetuses to reach their growth potential; however, metabolic mechanisms during pregnancy remain poorly understood. I propose to develop a methodology to study fetal brain and placental metabolism using high-resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS) in experimental mice. The mouse is the ideal pregnancy model to answer questions about metabolism because of the similarities between mouse and human fetal brain development and placental structure. While the results of 1H MRS studies in human pregnancy have been hampered by low signal sensitivity and low spectral resolution, there have been some intriguing findings. Here, the use of a high field magnet (600 MHz) combined with HRMAS will significantly improve our ability to measure known and novel metabolites in healthy fetal brain and placental tissue. HRMAS MRS of intact samples provides information about the location of metabolites in the tissue and, because it is non-destructive, allows the samples to subsequently be studied by other techniques to extract complementary cellular level information. The use of HRMAS MRS to study tissue biopsy samples from adult brain and other organs shows the tremendous promise of using this technique to study pregnancy. To date, the potential for MRS in mouse models of pregnancy has yet to be explored. Our first goal will be to establish the best way to collect tissue samples and to optimize the MR scan conditions to minimize changes to the tissue composition. We will then use this methodology to look at nuclei that are of high abundance in biological tissue such as 13C and 31P to provide a more complete metabolic profile of the tissue. Using innovative NMR experiments and data analysis such as the measurement of nuclear relaxation rates and unsupervised clustering analysis, we will aim to enhance the specificity and sensitivity of the MRS data by including quantitative NMR properties. Our study will include both male and female fetuses, allowing us to detect sex dependent effects. We will also look at whether there are differences in metabolite profile between different areas of the brain and placenta. Determination of the levels of brain and placental metabolites in healthy pregnancy and how they change throughout gestation is critical for understanding brain and placental function. This work will offer novel approaches for studying metabolism during pregnancy and, because MRS can be performed in utero, the basic research findings of this proposal can be translated to humans. Magnetic resonance imaging is routinely being used in pregnancy and the results of this study will provide a significant benefit to women's and fetal health through a better understanding of metabolism. This work will open avenues for potential diagnostics for early detection of metabolic abnormalities associated with pregnancy and monitoring of novel therapies.

在怀孕期间，适当的胎盘代谢对于胎儿发挥其生长潜力至关重要；然而，人们对怀孕期间的代谢机制仍知之甚少。我建议开发一种方法，在实验小鼠中使用高分辨率魔角旋转 (HRMAS) 磁共振波谱 (MRS) 研究胎儿大脑和胎盘代谢。由于小鼠和人类胎儿大脑发育和胎盘结构的相似性，小鼠是回答新陈代谢问题的理想妊娠模型。虽然人类妊娠 1H MRS 研究的结果因信号灵敏度低和光谱分辨率低而受到阻碍，但还是有一些有趣的发现。在这里，使用高场磁铁 (600 MHz) 与 HRMAS 相结合将显着提高我们测量健康胎儿大脑和胎盘组织中已知和新代谢物的能力。完整样品的 HRMAS MRS 提供有关组织中代谢物位置的信息，并且由于它是非破坏性的，因此允许随后通过其他技术对样品进行研究，以提取补充的细胞水平信息。使用 HRMAS MRS 研究成人大脑和其他器官的组织活检样本显示了使用该技术研究妊娠的巨大前景。迄今为止，MRS 在小鼠妊娠模型中的潜力尚未得到探索。 我们的首要目标是建立收集组织样本并优化 MR 扫描条件的最佳方法，以尽量减少组织成分的变化。然后，我们将使用这种方法来观察生物组织中高丰度的细胞核，例如 13C 和 31P，以提供更完整的组织代谢概况。利用创新的 NMR 实验和数据分析（例如核弛豫率测量和无监督聚类分析），我们的目标是通过纳入定量 NMR 特性来提高 MRS 数据的特异性和灵敏度。我们的研究将包括男性和女性胎儿，使我们能够检测性别依赖性影响。我们还将研究大脑和胎盘不同区域之间的代谢物谱是否存在差异。 确定健康妊娠期间大脑和胎盘代谢物的水平以及它们在整个妊娠过程中如何变化对于了解大脑和胎盘功能至关重要。这项工作将为研究妊娠期间的新陈代谢提供新的方法，并且由于 MRS 可以在子宫内进行，因此该提案的基础研究结果可以转化为人类。磁共振成像在怀孕期间常规使用，这项研究的结果将通过更好地了解新陈代谢为妇女和胎儿的健康带来重大益处。这项工作将为早期检测与妊娠相关的代谢异常和监测新疗法开辟潜在诊断途径。