Genetic Regulation of Hypoxia-Induced IUGR

描述（由申请人提供）：高海拔地区氧气供应减少限制了胎儿生长，增加了先兆子痫的发生频率，使高海拔居民成为这些并发症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）血流。此外，我们的数据表明，与短期高海拔居民相比，多代人由于更大的UA血流量而免受高度相关的IUGR增加的影响。基于最近的证据表明低氧诱导转录因子（HIF）在调节O2敏感基因中起核心作用，与妊娠障碍有关，以及我们的初步数据表明它们在长期与短期人群中受到差异调节，我们建议检验HIF靶向或调节途径中的遗传变异保护多代高海拔居民免受缺氧的总体假设-相关IUGR系列研究提出在怀孕期间和产后再次在100高（3600米）和100低（300米）海拔居民。妇女将从多代居住在高海拔地区的人口（安第斯人）和居住时间较短的人口（欧洲人）中平均分配。具体目的是测试1）安第斯与欧洲血统是否由于影响HIF靶向分泌基因产物和UA血流量的遗传因素而对缺氧诱导的IUGR具有保护作用，2）UA血流量和胎儿生长的差异是由于HIF靶向和调节基因，3）安第斯-欧洲人母体对妊娠和胎儿生长的生理反应的差异是HIF-1 α作用的结果。影响UA血管收缩、血管舒张或生长的靶向或调节基因。这些目标得到了初步数据的支持，这些数据表明安第斯山脉与欧洲高海拔居民的缺氧相关IUGR保护，以及更大的UA血流量，更低的内皮素-1水平（EDN 1）和EDN 1中或附近的独特遗传变异的存在以及其他HIF靶向基因。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，以确定影响母体血管对妊娠和缺氧诱导的IUGR反应的基因。拟议的研究不仅与全球1.4亿高海拔居民有关，包括科罗拉多的10多万人，而且与大量妊娠并发子宫胎盘缺血和/或胎儿缺氧的妇女有关。

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.