EFFECT OF HYPERGLYCEMIA ON NEURALATING MOUSE EMBRYOS

高血糖对神经小鼠胚胎的影响

• 批准号: 7953823
• 负责人: MARY R LOEKEN
• 金额: $ 0.56万
• 依托单位: MARINE BIOLOGICAL LABORATORY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953823
• 关键词: Adverse effects; Biochemical; Biological Assay; Blood Circulation; Boston; Cell Respiration; Complications of Diabetes Mellitus; Computer Retrieval of Information on Scientific Projects Database; Congenital Abnormality; Consumption; Development; Disease; Embryo; Embryonic Development; Environment; Funding; Future; Gene Expression; Glucose; Grant; Hour; Hyperglycemia; Hypoxia; Institution; Laboratories; Lead; Measurement; Metabolic; Molecular; Mus; National Center for Research Resources; Pathogenesis; Pathway interactions; Pregnancy; Research; Research Personnel; Resources; Signal Transduction; Source; Staging; Testing; Time; United States National Institutes of Health; Wood material; diabetic; diabetic embryopathy; glucose metabolism; insight; maternal diabetes; non-diabetic; prevent; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are investigating the molecular causes of birth defects induced by diabetic pregnancy. We have previously shown that birth defects, which occur 3-5 times more frequently in diabetic, than in nondiabetic pregnancies, are caused by increased glucose metabolism by the embryo, resulting from increased delivery of glucose from maternal circulation to the embryo. Increased glucose metabolism by the embryo impairs expression of genes which are necessary for structural development. At the stage of development that is susceptible to diabetic pregnancy-induced birth defects, the embryo is not yet vascularized and exists in a hypoxic environment (2-8% O2, compared to 20% O2 in post-natal arterial circulation). Thus, we hypothesized that increased glucose metabolism by the embryo could consume O2 faster than it could be replenished. This research has relevance to disease, because the biochemical and molecular causes of diabetic embryopathy are poorly understood, and understanding whether O2 consumption contributes to the pathogenesis of this diabetic complication may lead to therapies to prevent it. In prior studies at the NCRR BioCurrents Research Center, we found that after 3 hours of maternal hyperglycemia, O2 flux, an indicator of aerobic metabolism, was significantly suppressed. Since aerobic metabolism depends on O2 availability, suppression of O2 flux indicates that, consistent with the hypothesis, excess glucose delivery to the embryo led to O2 consumption in excess of delivery. We have obtained additional evidence that restricting O2 delivery to embryos at the same stage of development replicates the adverse effects of maternal diabetes on embryogenesis, supporting the hypothesis that increased glucose metabolism consumes O2 faster than it can be repleted. In future experiments, we propose to assay O2 and glucose flux at rapid time points after induction of maternal hyperglycemia, to further test the hypothesis that increased oxidative glucose metabolism depletes O2 utilization. There is no other resource that I know of which can provide such measurements. Given the proximity of our laboratory in Boston, MA, to the BioCurrents Laboratory in Woods Hole, MA, this is a rare opportunity to characterize maternal hyperglycemia-induced O2 and glucose utilization. These studies are highly significant, not only because they provide biochemical insights into the causes of birth defects induced by diabetic pregnancy, but because they implicate metabolic signaling (i.e. O2 utilization), in activation of developmental control pathways.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 我们正在研究糖尿病妊娠引起的先天缺陷的分子原因。我们先前已经表明，糖尿病患者的出生缺陷比非糖尿病妊娠的发生频率高3-5倍，是由于胚胎的葡萄糖代谢增加引起的，这是由于葡萄糖从母体循环到胚胎的增加而引起的。胚胎通过胚胎的表达增加了葡萄糖代谢，这是结构发育所必需的。在易感糖尿病妊娠引起的先天缺陷的发育阶段，胚胎尚未血管化，并且在低氧环境中存在（2-8％O2，而产后动脉循环中为20％O2）。因此，我们假设胚胎增加的葡萄糖代谢增加的速度可能比可以补充的葡萄糖代谢更快。这项研究与疾病有关，因为糖尿病胚胎病的生化和分子原因知之甚少，并且了解O2消耗是否有助于这种糖尿病并发症的发病机理，可能会导致疗法阻止它。 在NCRR Biocurrents研究中心的先前研究中，我们发现经过3个小时的母体高血糖，O2通量（有氧代谢的指标）受到了显着抑制。由于有氧代谢取决于O2的可用性，因此O2通量的抑制表明，与假设相一致，向胚胎过量葡萄糖递送过多导致O2的消耗量超过递送。我们获得了其他证据表明，在发育的同一阶段将O2递送到胚胎的递送复制了母体糖尿病对胚胎发生的不利影响，这支持了以下假设，即增加葡萄糖代谢会比它更快地消耗O2。 在将来的实验中，我们建议在诱导母体高血糖诱导后的快速时间点测定O2和葡萄糖通量，以进一步检验以下假设，即增加氧化葡萄糖代谢耗尽O2的利用率。我没有其他资源可以提供此类测量。鉴于我们在马萨诸塞州波士顿的实验室与马萨诸塞州伍兹孔的生物流实验室的距离，这是表征母体高血糖诱导的O2和葡萄糖利用的难得的机会。 这些研究非常重要，这不仅是因为它们为糖尿病妊娠引起的先天缺陷提供了生化见解，而且还因为它们牵涉到代谢信号传导（即O2利用率），以激活发育控制途径。