Genetic Regulation of Hypoxia-Induced IUGR

缺氧引起的 IUGR 的基因调控

• 批准号: 7124162
• 负责人: LORNA G. MOORE
• 金额: $ 7.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7124162
• 关键词: alleles; clinical research; embryogenesis; gene expression; genetic susceptibility; guinea pigs; hemodynamics; human birth weight; human population genetics; human pregnant subject; hypoxia; natural selections; pregnancy circulation; prenatal growth disorder; protein metabolism; regulatory gene; residential mobility; single nucleotide polymorphism; tissue /cell culture; transcription factor; vascular resistance; women' s health

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.

描述（由申请人提供）：高海拔地区 02 的可用性降低会限制胎儿生长并增加先兆子痫的发生率，使高海拔居民成为这些并发症风险最大的群体。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所致。生长和重塑会减少子宫动脉（UA）血流量。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血流量增加而免受与海拔相关的IUGR增加的影响。根据最近的证据表明，缺氧诱导转录因子（HIF）在调节 O2 敏感基因中发挥着核心作用，与妊娠疾病有关，并且我们的初步数据表明它们在长期与短期人群中受到不同的调节，我们建议检验以下总体假设：HIF 靶向或调节途径中的遗传变异可保护多代高海拔居民免受缺氧相关的 IUGR 的影响。建议在怀孕期间和产后对 100 名高海拔（3600 m）和 100 名低海拔（300 m）居民进行系列研究。女性将均匀地从多代（安第斯）和短期（欧洲）居住在高海拔地区的人群中抽取。具体目的是测试 1) 安第斯血统与欧洲血统是否对缺氧引起的 IUGR 有保护作用，因为遗传因素影响 HIF 靶向分泌基因产物和 UA 血流，2) UA 血流和胎儿生长的差异是由于 HIF- 3) 安第斯-欧洲人对妊娠和胎儿生长的母体生理反应的差异是影响 UA 的 HIF 靶向或调节基因作用的结果血管收缩、血管舒张或生长。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，安第斯山脉居民可以免受缺氧相关的 IUGR 的影响，同时具有更大的 UA 血流量、更低的内皮素-1 水平 (EDN1) 以及 EDN1 内或附近存在独特的遗传变异以及其他 HIF 靶向基因。因此，我们设计了一种新策略，将基因组方法与更传统的生理学工具结合起来，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 亿高海拔地区居民相关，其中包括科罗拉多州的 10 万多人，而且还与大量因子宫胎盘缺血和/或胎儿缺氧而怀孕的女性相关。