Maternal extracellular vesicles as key mediators of fetal growth and offspring cardiometabolic health in pregnancies complicated by type-1 diabetes.

母体细胞外囊泡是妊娠并发 1 型糖尿病时胎儿生长和后代心脏代谢健康的关键介质。

• 批准号: MR/Y003659/1
• 负责人: Karen Forbes
• 金额: $ 99.03万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY003659%2F1
• 关键词: Maternal; extracellular; vesicles; key; mediators

Diabetes affects 1-2% of pregnancies and increases the risks of pregnancies for mothers and babies. Women with diabetes are five times more likely to have stillbirths. Diabetes can affect babies' growth- being too big or too small increases their risks of stillbirths. National Audit data shows that 57% of babies born to mothers with Type 1 diabetes mellitus (T1DM) are bigger than normal, known as large for gestational age (LGA; birth weight >90% centile). Big babies are more likely to experience injury during birth and are more likely to develop obesity, diabetes or heart disease in later life. Until recently, it was thought that babies were growing bigger because the high levels of glucose in mothers blood were crossing the placenta to cause babies to growth more. However, recently it has been shown that even in mothers who are treated to achieve very tight glucose control, women with T1DM are still at very high risk of having and LGA baby. The NHS Long Term Plan, alongside with the Royal College of Obstetricians and Gynaecologists (RCOG) and James Lind Alliance Priority Setting Partnership have identified the importance of improving pregnancy care and diabetes prevention and management. Given the increasing number of pregnancies affected by diabetes and the impact that it has on the life-long-health of babies, there is a crucial need to understand how diabetes in pregnancy affects baby's growth and function of placenta, so we can identify potential new treatments.Recently, our research team was part of a large international clinical trial,which was undertaken using state-of-the-art technology (CGM), to monitor glucose in pregnant women with type 1 diabetes (CONCEPTT). This study showed that that very small differences in maternal glucose throughout the day (undetectable by other methods) are linked to large babies in women with T1DM. However, the mechanisms through which these small differences in glucose affect baby's growth and function of placenta are unclear. We have shown in the lab, that these very small changes in glucose can cause some changes to the placenta, but they don't explain why babies grow so big. Using CGM to measure glucose levels over the whole day/night has shown that small differences in maternal glucose throughout the day are linked to large babies in women with T1DM. Our team has recent data that molecules known as microRNAs (miRNAs) contained in small bubble-like particles, called extracellular vesicles (EVs) in mother's blood are increased in pregnant women before babies become big in gestational diabetes mellitus (GDM). We have shown that some of these EV-miRNAs originate from maternal organs in relation to glucose levels. These EVs/miRNAs can travel to the placenta and affect how placenta grows and functions. We think this may be even more relevant in women with T1DM who are more likely to have big babies. Our team has access to data and stored samples of mother's blood obtained from the CONCEPTT trial and we will use these samples to look at the different messages contained within EVs. We will then look at how the content of EVs is linked to glucose and LGA, and we will use human placentas to determine if EVs are causing placentas to develop abnormally. We will then do studies in pregnant mice test whether EVs and the messages contained within them, can potentially cause babies to become bigger, and if they affect how different organs such as heart and pancreas develop in the baby, and if it affect their risk of getting diabetes, obesity or heart disease in later life. If as we suspect, EVs do cause changes to the way the placenta and baby develop, will help us to design treatments to decrease the short and long term effects of GDM and to reduce the chance of babies developing obesity, cardiovascular disease or diabetes in adulthood.

糖尿病影响 1-2% 的怀孕，并增加母亲和婴儿的怀孕风险。患有糖尿病的女性死产的可能性是其他女性的五倍。糖尿病会影响婴儿的生长——太大或太小都会增加死产的风险。国家审计数据显示，患有 1 型糖尿病 (T1DM) 的母亲所生的婴儿中有 57% 比正常婴儿大，称为大于胎龄 (LGA；出生体重 >90% 百分位数)。大婴儿在出生时更有可能受到伤害，并且在以后的生活中更有可能患上肥胖、糖尿病或心脏病。直到最近，人们还认为婴儿长得更大是因为母亲血液中的高水平葡萄糖穿过胎盘导致婴儿长得更大。然而，最近的研究表明，即使在接受治疗以实现非常严格的血糖控制的母亲中，患有 T1DM 的女性生下 LGA 婴儿的风险仍然非常高。 NHS 长期计划与皇家妇产科学院 (RCOG) 和詹姆斯林德联盟优先设定合作伙伴关系已经确定了改善妊娠护理和糖尿病预防和管理的重要性。鉴于受糖尿病影响的妊娠人数不断增加及其对婴儿终生健康的影响，迫切需要了解妊娠期糖尿病如何影响婴儿的生长和胎盘功能，以便我们能够识别潜在的新疾病最近，我们的研究团队参与了一项大型国际临床试验，该试验采用最先进的技术 (CGM) 进行，旨在监测 1 型糖尿病孕妇的血糖 (CONCEPTT)。这项研究表明，母亲全天血糖的微小差异（其他方法无法检测到）与 1 型糖尿病女性的大婴儿有关。然而，这些葡萄糖的微小差异影响婴儿生长和胎盘功能的机制尚不清楚。我们在实验室中证明，葡萄糖的这些非常小的变化可能会导致胎盘发生一些变化，但它们并不能解释为什么婴儿长得这么大。使用 CGM 测量全天/夜间的血糖水平表明，全天母亲血糖的微小差异与 1 型糖尿病女性的大婴儿有关。我们团队最近的数据表明，在妊娠期糖尿病 (GDM) 中，在婴儿变大之前，孕妇血液中的小气泡状颗粒（称为细胞外囊泡 (EV)）中含有的微小 RNA (miRNA) 分子会增加。我们已经证明，其中一些 EV-miRNA 源自与葡萄糖水平相关的母体器官。这些 EV/miRNA 可以进入胎盘并影响胎盘的生长和功能。我们认为这对于患有 T1DM 的女性来说可能更有意义，因为她们更有可能生出大婴儿。我们的团队可以访问从 CONCEPTT 试验中获得的数据和存储的母亲血液样本，我们将使用这些样本来查看 EV 中包含的不同信息。然后我们将研究 EV 的含量如何与葡萄糖和 LGA 相关，并且我们将使用人类胎盘来确定 EV 是否导致胎盘发育异常。然后，我们将对怀孕的小鼠进行研究，测试电动汽车及其中包含的信息是否可能导致婴儿变大，它们是否会影响婴儿心脏和胰腺等不同器官的发育，以及是否会影响婴儿的风险。在晚年患上糖尿病、肥胖症或心脏病。如果像我们怀疑的那样，EV 确实会改变胎盘和婴儿的发育方式，将有助于我们设计治疗方法，以减少 GDM 的短期和长期影响，并减少婴儿在成年后患肥胖、心血管疾病或糖尿病的机会。