Genetic Regulation of Hypoxia-Induced IUGR

描述(由申请人提供)：在高海拔地区氧气供应减少限制了胎儿生长并增加了先兆子痫的发生率，使高海拔居民成为这些并发症的风险最大的单一群体。我们已经证明，这种与海拔高度相关的增加，部分是由于母体血管反应性的改变；生长和重塑，减少了子宫动脉(UA)的血流。此外，我们的数据表明，与短期居住的高海拔居民相比，多代人居住在高海拔地区可以避免因UA血流量增加而导致的IUGR增加。基于最近的证据表明，低氧诱导转录因子(HIF)在调节O2敏感基因中发挥核心作用，与妊娠障碍有关，并且我们的初步数据表明，它们在长期和短期人群中存在差异调节，我们建议检验这一总体假设，即HIF靶向或调节途径中的基因变异保护多代高海拔居民免受缺氧相关IUGR的影响。对100名高海拔(3600米)和100名低海拔(300米)居民进行了孕期和产后的系列研究。女性将平均从居住在高海拔地区的多代(安第斯)和短期(欧洲)人口中挑选出来。具体目的是测试1)安第斯血统和欧洲血统是否对缺氧诱导的IUGR具有保护作用，原因是遗传因素影响HIF靶向分泌基因产物和UA血流，2)UA血流量和胎儿生长的差异是由于HIF靶向和调控基因，以及3)安第斯-欧洲血统对怀孕和胎儿生长的母体生理反应的差异是HIF靶向或调控基因影响UA血管收缩、血管扩张或生长的作用的结果。这些目标得到了初步数据的支持，这些数据表明，与欧洲高海拔居民相比，安第斯人对低氧相关的IUGR具有保护作用，同时UA血流量更大，内皮素-1水平(EDN1)更低，EDN1以及其他HIF靶向基因中或附近存在独特的遗传变异。因此，我们设计了一种新的策略，将基因组方法与更传统的生理工具相结合，以确定影响孕妇对怀孕和低氧诱导的IUGR的血管反应的基因。拟议中的研究不仅涉及全球1.4亿高海拔居民，其中包括科罗拉多州的10万多人，而且还涉及更多怀孕合并子宫胎盘缺血和/或胎儿缺氧的女性。

DESCRIPTION (provided by applicant): Reduced 02 availability at high altitude restricts fetal growth and increases the frequency of preeclampsia, making high-altitude residents the single largest group at risk for these complications. We have shown that this altitude-related increase is due, in part, to alterations in maternal vascular reactivity; growth and remodeling that lessen uterine artery (UA) blood flow. Moreover our data demonstrate that multigenerational compared with shorter-term high-altitude residents are protected from the altitude-associated increase in IUGR due to greater UA blood flow. Based on recent evidence demonstrating that hypoxia-inducible transcription factors (HIFs) play a central role in regulating O2-sensitive genes, are implicated in pregnancy disorders, and our preliminary data that they are differentially regulated in long- vs. short-term populations, we propose to test the overall hypothesis that genetic variants in HIF-targeted or regulatory pathways protect multigenerational high-altitude residents from hypoxia-associated IUGR. Serial studies are proposed during pregnancy and again postpartum in 100 high- (3600 m) and 100 low- (300 m) altitude residents. Women will be drawn evenly from populations with multigenerational (Andean) vs. shorter-term (European) residence at high altitude. Specific aims are to test whether 1) Andean vs. European ancestry is protective against hypoxia-induced IUGR due genetic factors influencing HIF-targeted secretory gene products and UA blood flow, 2) differences in UA blood flow and fetal growth are due to HIF-targeted and -regulatory genes, and 3) Andean-European differences in maternal physiologic responses to pregnancy and fetal growth are the result of actions of HIF-targeted or regulatory genes influencing UA vasoconstriction, vasodilation, or growth. These aims are supported by preliminary data demonstrating protection from hypoxia-associated IUGR in Andean vs. European high-altitude residents together with greater UA blood flow, lower endothelin-1 levels (EDN1) and the presence of distinctive genetic variants in or near the EDN1 as well as other, HIF-targeted genes. Thus we have designed a novel strategy for coupling genomic approaches with more traditional physiological tools to identify genes influencing maternal vascular response to pregnancy and hypoxia-induced IUGR. The proposed studies are relevant not only for the 140 million high-altitude residents worldwide, including more than 100,000 in Colorado, but also the larger number of women whose pregnancies are complicated by uteroplacental ischemia and/or fetal hypoxia.