宫内慢性缺氧对子代脂质代谢的影响及其早期超声定量诊断的建立

Intrauterine chronic hypoxia increases the risk of cardiovascular disease in later life. Abnormal lipid metabolism is one of the main factors induced cardiovascular disease. However, the relationship between intrauterine chronic hypoxia and the occurrence of abnormal lipid metabolism in later life is remain unclear, the early non-invasive and accurate diagnosis of fetal hypoxia need to be studied as well. The present project aims to study the role of chronic intrauterine hypoxia on the lipid metabolism in the offspring and explore a new imaging method for early diagnosis of fetal hypoxia. Firstly, the lipid metabolism-related genes which programmed by intrauterine chronic hypoxia will be sreened by using a high-throughput gene chip technology in the offspring of intrauterine chronic hypoxia. Secondly, the role of intrauterine chronic hypoxia on insulin resistance and lipid metabolism of liver in the offspring and its mechanisms will be studied, the potential gender-dependent differences of these effects will be explored as well. Further more, the mechanisms of intrauterine chronic hypoxia induced abnormal lipid metabolism in the offspring which mediated by insulin resistance will be elucidated. Finally, the ultrasound prediction system of fetal hypoxia (quantify extent system of Doppler ultrasound) will be conducted by using a fetal sheep hypoxia model, and the early non-invasive accurate diagnosis of fetal hypoxia and Hypoxic Ischemic Encephalopathy by a method of ultrasound combined with MRI will be established in a case control study.

宫内慢性缺氧可增加日后成年期发生心血管疾病风险，脂质代谢异常是诱发心血管疾病的主要因素之一，然而，宫内慢性缺氧与日后发生脂质代谢异常之间的关系仍不清楚，早期无创准确地诊断胎儿缺氧亦有待研究。本项目旨在研究宫内慢性缺氧对出生后子代脂质代谢的影响并探索影像学早期诊断胎儿缺氧的新方法。首先，通过大鼠宫内慢性缺氧模型，采用高通量基因芯片技术筛选宫内慢性缺氧程序性调控的子代脂质代谢相关基因；其次研究宫内慢性缺氧对子代出生后胰岛素抵抗和肝脏脂质代谢的影响及其机制，并探索该效应的潜在性别依赖性差异；随后进一步探索胰岛素抵抗介导宫内慢性缺氧诱导的子代脂质代谢异常的具体机制；最后，通过胎羊缺氧模型，完善胎儿缺氧的超声检查预测体系（Doppler超声严重程度的量化体系），并通过临床病例对照研究，建立超声检查联合MRI技术早期、无创、准确地诊断胎儿缺氧和预测新生儿缺血缺氧性脑病的新方法。

项目背景：近十几年来，越来越多的证据显示：成年期慢性疾病发生的危险受作用于生命早期组织可塑性生长发育特异时间窗的环境因素明显影响。宫内缺氧是最常见、最重要的胎儿不良环境应激，与子代罹患多种慢性代谢性疾病息息相关。此外胎儿缺氧还是引起围生期残障和死亡的主要原因。综上所述，胎儿宫内缺氧的程序性控制机制研究以及早期超声筛查方法的建立尤为重要。主要研究内容：1.构建大鼠慢性宫内缺氧模型、高脂饮食动物模型、久坐动物模型和有氧运动模型等，研究慢性宫内缺氧与子代慢性代谢性疾病的关系；2. 运用数字化基因表达谱技术，从全基因组水平筛查差异表达的目的基因，生物信息学分析进一步筛选宫内慢性缺氧程序性调控的子代脂质代谢相关基因；3. 从胰岛素抵抗角度、糖脂代谢调节角度等，探索宫内慢性缺氧与子代慢性代谢性疾病的关系，以及出生后早期运动干预的再编程作用；4. 建立DUPS+HI 和Doppler 超声评估宫内慢性缺氧严重程度的量化体系。重要结果、关键数据：1. 成功建立相关动物模型，建模方法简单易行，成模率高，模型稳定。本课题研究发现慢性宫内缺氧增加子代大鼠非酒精性脂肪肝病、高血脂、动脉粥样硬化等慢性代谢性疾病的易感性。2. 通过差异表达基因的生物信息学分析，确定慢性宫内缺氧可程序性控制子代新生雄鼠骨骼肌基因的差异表达。3. 慢性宫内缺氧可以程序性引起子代新生雄鼠糖脂代谢编程改变，其中部分代谢性适应仅存在于新生儿期。胰岛素信号通路上调、脂肪酸氧化抑制以及线粒体生物合成标志分子UCP-2下调都参与了宫内编程。代谢失调表型可以由青少年期运动训练部分逆转，说明慢性宫内缺氧诱导的子代慢性代谢性疾病倾向能够被青少年期不同活动模式“再编程”。4. 建立DUPS+HI 和Doppler 超声评估宫内慢性缺氧严重程度的量化体系。科学意义：本课题研究发现慢性宫内缺氧与子代大鼠非酒精性脂肪肝病、高血脂、动脉粥样硬化等慢性代谢性疾病的发生、发展密切相关；揭示了慢性宫内缺氧程序性调控子代基因差异表达，胰岛素代谢及糖脂代谢编程作用显著；慢性宫内缺氧诱导的代谢紊乱倾向能被青少年期不同活动模式“再编程”；胎儿缺氧的超声预测及评估体系得到全面完善。