Genetic Regulation of Hypoxia-Induced IUGR

描述（由申请人提供）：高海拔地区02可用性降低限制了胎儿生长，增加了先兆子痫的频率，使高海拔地区居民成为这些并发症风险最大的单一群体。我们已经证明，这种与海拔相关的增加部分是由于母体血管反应性的改变；减少子宫动脉（UA）血流的生长和重塑。此外，我们的数据表明，与短期高海拔居民相比，多代人由于UA血流量增加而免受海拔相关IUGR增加的影响。最近有证据表明，缺氧诱导转录因子（hif）在调节o2敏感基因中起着核心作用，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受到不同的调节，我们建议验证hif靶向或调节途径的遗传变异保护多代高海拔居民免受缺氧相关IUGR的总体假设。对100名高海拔（3600米）和低海拔（300米）居民进行了孕期和产后的系列研究。女性将从多代（安第斯人）和短期（欧洲人）居住在高海拔地区的人口中平均抽取。具体目的是测试1)安第斯人与欧洲人血统是否由于影响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hif靶向和调节基因引起的，3)安第斯人和欧洲人母亲对妊娠和胎儿生长的生理反应差异是hif靶向或调节基因影响UA血管收缩的结果。血管扩张，或生长。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地区的居民在缺氧相关的IUGR中具有保护作用，同时UA血流量更大，内皮素-1水平（EDN1）更低，EDN1中或附近存在独特的遗传变异，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（包括科罗拉多州的10万多名）有关，而且与大量因子宫胎盘缺血和/或胎儿缺氧而导致妊娠并发症的妇女有关。

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.