Genetic Regulation of Hypoxia-Induced IUGR

缺氧引起的 IUGR 的基因调控

基本信息

批准号：
7619344
负责人：
LORNA G. MOORE
金额：
$ 13.37万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7619344
关键词：
Abbreviations Altitude American Arteries Binding Biological Assay Blood Blood Vessels Blood Volume Blood flow Caliber Cell Hypoxia Chronic Colorado Condition Constriction procedure Coupling Data Endothelial Cells Endothelin-1 Erythropoietin Etiology European Fetal Growth Fetal Growth Retardation Frequencies Gene Frequency Gene Targeting Genes Genetic Genetic Markers Genetic Variation Genomics Growth Growth Factor Haplotypes Human Genome Hypoxia Hypoxia Inducible Factor Hypoxia-Responsive Elements In Vitro Indigenous Ischemia Laboratories Length Linkage Disequilibrium Luciferases Measures Membrane Messenger RNA Natural Selections Nature Nitric Oxide Synthase Numbers PGF gene Peripheral Resistance Personal Satisfaction Physiological Physiology Play Population Postpartum Period Pre-Eclampsia Predisposition Pregnancy Process Procollagen-Proline Dioxygenase Proteins Regulation Regulator Genes Regulatory Pathway Reporting Resistance Risk Role Sea Single Nucleotide Polymorphism Smooth Muscle Myocytes Study Subject System Tamoxifen Testing Time Variant Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular resistance Vasodilation Woman base design fetal fetus hypoxia genetic variant hemodynamics indexing novel strategies pregnancy disorder promoter research study residence response sex tool transcription factor vasoconstriction

项目摘要

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.

高海拔地区 02 利用率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、生长和发育的改变。重塑减少子宫动脉（UA）血流量。此外，我们的数据表明与短期高海拔居民相比，多代同堂的高海拔居民受到保护由于 UA 血流量增加，与海拔高度相关的 IUGR 增加。根据最近的证据证明缺氧诱导转录因子（HIF）在调节中发挥核心作用 O2 敏感基因与妊娠疾病有关，我们的初步数据表明它们是由于长期与短期人群的监管存在差异，我们建议检验以下总体假设： HIF 靶向或调控途径中的遗传变异可保护多代高海拔居民来自缺氧相关的 IUGR。建议在怀孕期间和产后进行系列研究 100 名高海拔（3600 m）和 100 名低海拔（300 m）居民。女性将均匀地从在高海拔地区多代（安第斯）居住的人口与短期（欧洲）居住的人口。具体目的是测试 1) 安第斯山与欧洲血统是否能够预防缺氧引起的 IUGR 由于遗传因素影响 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 靶向和调节基因造成的，3) 安第斯山脉和欧洲人对怀孕和胎儿生长的母亲生理反应的差异是 HIF 靶向基因或调节基因影响 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，这些数据证明了对缺氧相关的保护作用安第斯山脉的 IUGR 与欧洲高海拔居民相比，UA 血流量更大，UA 血流量更低内皮素-1 水平 (EDN1) 以及 EDN1 内或附近是否存在独特的遗传变异以及其他 HIF 靶向基因。因此，我们设计了一种耦合基因组方法的新策略使用更传统的生理学工具来识别影响母体血管反应的基因妊娠和缺氧引起的 IUGR。拟议的研究不仅与 1.4 亿人相关全世界的高海拔居民，其中科罗拉多州有超过 100,000 人，而且数量也更多妊娠并发子宫胎盘缺血和/或胎儿缺氧的女性。