Genetic Regulation of Hypoxia-Induced IUGR

缺氧引起的 IUGR 的基因调控

• 批准号: 7011187
• 负责人: LORNA G. MOORE
• 金额: $ 50.36万
• 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/7011187
• 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）：在高海拔地区降低02可用性可限制胎儿的生长并增加子痫前期的频率，使高空居民成为有可能发生这些并发症的最大群体。我们已经表明，这种与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，减轻了子宫动脉（UA）的血流。此外，我们的数据表明，与较短的高海拔居民相比，由于UA的血流较大，因此，与较短的高海拔居民相比，受IUGR的高度相关增加。基于最近的证据表明，缺氧诱导的转录因子（HIF）在调节O2敏感基因的调节中起着核心作用，与妊娠疾病有关，我们的初步数据在长期与短期人群中受到差异性调节，我们建议在跨性别的途径中测试跨性别的途径，从而在跨性别的途径中进行跨性别的假设。缺氧相关的IUGR。在怀孕期间提出了串行研究，并在100个高（3600 m）和100个低 - （300 m）高度居民中再次产后产后。妇女将从高海拔地区的多代（安第斯）与短期（欧洲）居住的人群中均匀地吸引。具体目的是测试1）Andean vs.欧洲血统是否针对缺氧引起的IUGR应有的遗传因素影响影响HIF靶向HIF的分泌基因产物和UA血流，2）UA血液流量和胎儿的差异是由HIF靶向的，并且涉及HIF的生长以及捕获元素的作用以及3）和效率的体现，以及3）和3）和效率的效果。受HIF靶向或调节基因影响UA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，证明了在安第斯与欧洲高空居民中与缺氧相关的IUGR的保护，以及更大的UA血液流动，下皮素-1水平（EDN1）以及EDN1或其他与HIF的基因相关的独特遗传变异。因此，我们设计了一种新型策略，用于将基因组方法与更传统的生理工具耦合，以鉴定影响母体血管反应对妊娠和缺氧引起的IUGR的基因。拟议的研究不仅与全世界的1.4亿高海拔居民有关，其中包括科罗拉多州的100,000多个居民，而且还与大量的妇女相关，其孕妇的怀孕因子宫遗传性缺血和/或胎儿缺氧而复杂化。