Evolved placental response to hypoxa

胎盘对缺氧反应的演变

基本信息

批准号：
8254398
负责人：
Derek Wildman
金额：
$ 24.33万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254398
关键词：
Admission activity Admixture Altitude Biological Assay Biological Markers Biology Birth Candidate Disease Gene Chronic Clinical Complex Coronary heart disease DNA DNA Resequencing Data Databases Development Diagnosis Disadvantaged Disease Engineering Environment Epigenetic Process Ethics European Evolution Fetal Death Fetal Growth Fetal Growth Retardation Fetus Future Gene Expression Gene Expression Profile Gene Family Genes Genetic Genetic Variation Genome Goals Growth Health Human Human Pathology Hypertension Hypoxia Intensive Care Investigation Life Link Maps Medical Methods Methylation Modeling Modification Molecular Mutation Native Americans Natural Selections Newborn Infant Nomads Non-Insulin-Dependent Diabetes Mellitus Organ Outcome Oxygen Oxygen measurement, partial pressure, arterial Pathology Pattern Perinatal Phase Phenotype Physiological Placenta Population Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Outcome Process Proteins Research Design Resistance Resolution Risk Sea Source Stress Stroke System Term Birth Testing Therapeutic Time Tissues Translational Research Variant Woman Work base bisulfite body system clinical Diagnosis clinically relevant comparative cost design disability disorder risk gene environment interaction genome wide association study genome-wide high risk improved in utero novel strategies population based pressure public health relevance research study residence response social therapy design trait transcription factor

项目摘要

DESCRIPTION (provided by applicant): Placental hypoxia contributes to major pregnancy complications such as intrauterine growth restriction (IUGR) and preeclampsia (PE). Globally, ~10% of all maternal/fetal deaths and ~ 20% of all NICU admissions are due to PE and/or IUGR. Fetoplacental hypoxia also increases the risk of coronary heart disease, type 2-diabetes, hypertension and stroke later in life. These major human health problems require new paradigms for understanding and resolution. Our goal is to identify evolved adaptations that protect the fetus from an adverse environment (hypoxia) within a particular organ system, the human placenta. The 4-group research design compares Andeans (altitude-adapted for ~8000 yr) versus altitude-naove (European) groups living at high versus low altitude. We are using an approach previously untested in the setting of recent human evolution, one of potentially high translational impact. This exploratory project will advance the fields of perinatal biology and evolutionary genetics forward in three ways. First we use a reverse engineering approach: rather than ask what causes disease, we ask what permits normal function under conditions that would normally increase disease risk. Identification of placental genes and systems that have been altered under the selective pressure of chronic (altitude-induced) hypoxia will demonstrate the utility of this approach. Second, for the first time, we apply analyses originally developed to detect genetic variation due to evolutionary forces between species to a within-species (human), organ specific (placenta) model in which the negative selective pressure (hypoxia) is known. Third, we seek to link the genetic variation detected with the physiological advantages we have previously identified as contributing to improved fetal growth and pregnancy outcome among the adapted Andean population. We will test this preliminarily in this proposal, and mechanistically in our future work. We can demonstrate the utility of this novel approach within the 2-year project because we already have an extensive clinical database, placental tissue and DNA from >200 pregnancies of known, genetically verified bio-geographic ancestry. The specific aims are: 1) Assess gene expression differences between adapted vs. altitude native groups in ~1500 genes expressed in human placenta previously identified as recently and adaptively evolving, and in those that we have identified as candidate genes based on our physiological studies of placental function; 2) Identify the source of the expression differences identified in Aim 1 by testing whether they are due to genetic or epigenetic effects. Our analytical approach includes tests designed to reveal the degree to which genes have been under selective pressure, permitting us to isolate effects due to ancestry vs. environment. The translational promise of such work is that we will identify adaptive evolutionary responses to hypoxic stress that can then be evaluated for therapeutic relevance in the treatment of pathological conditions at sea level. ) PUBLIC HEALTH RELEVANCE: Abnormalities of human fetal growth cost billions of dollars per year in intensive care for newborns and subsequent medical and social costs due to disabilities. This project is designed to discover placental genes that have specifically evolved to protect babies in utero from the consequences of not enough oxygen in the placenta. This will provide us with a map for the development of clinical tests that detect when babies in utero are not growing normally and to design therapies to improve their growth and long-term health.

描述（由申请人提供）：胎盘缺氧会导致主要妊娠并发症，例如宫内生长受限（IUGR）和先兆子痫（PE）。在全球范围内，约 10% 的孕产妇/胎儿死亡和约 20% 的 NICU 入院病例是由 PE 和/或 IUGR 造成的。胎儿胎盘缺氧还会增加日后患冠心病、2型糖尿病、高血压和中风的风险。这些重大的人类健康问题需要新的范式来理解和解决。我们的目标是确定进化的适应性，以保护胎儿免受特定器官系统（人类胎盘）内的不利环境（缺氧）的影响。 4组研究设计比较了安第斯山脉（适应海拔约8000年）与生活在高海拔和低海拔地区的海拔新手（欧洲）群体。我们正在使用一种以前未经在最近的人类进化环境中测试过的方法，这是一种潜在的高转化影响。这个探索性项目将从三个方面推动围产期生物学和进化遗传学领域的发展。首先，我们使用逆向工程方法：我们不问是什么导致了疾病，而是问在通常会增加疾病风险的条件下，是什么允许正常功能。鉴定在慢性（海拔引起的）缺氧的选择压力下发生改变的胎盘基因和系统将证明这种方法的实用性。其次，我们首次将最初开发的用于检测由于物种间进化力引起的遗传变异的分析应用到物种内（人类）、器官特异性（胎盘）模型，其中负选择压力（缺氧）是已知的。第三，我们试图将检测到的遗传变异与我们之前确定的生理优势联系起来，这些优势有助于改善适应的安第斯人群中的胎儿生长和妊娠结局。我们将在本提案中对此进行初步测试，并在未来的工作中机械地进行测试。我们可以在为期 2 年的项目中展示这种新方法的实用性，因为我们已经拥有广泛的临床数据库、胎盘组织和 DNA，这些数据来自超过 200 例已知的、经过基因验证的生物地理血统的妊娠。具体目标是： 1) 评估适应群体与海拔本地群体之间约 1500 个基因表达的差异，这些基因在人类胎盘中表达，这些基因先前被确定为最近和适应性进化的，以及我们根据我们的生理学研究确定为候选基因的基因。胎盘功能； 2) 通过测试目标 1 中确定的表达差异是否归因于遗传或表观遗传效应，确定其来源。我们的分析方法包括旨在揭示基因受到选择压力的程度的测试，使我们能够分离出祖先与环境造成的影响。此类工作的转化前景是，我们将确定对缺氧应激的适应性进化反应，然后可以评估其在海平面病理状况治疗中的治疗相关性。）公共卫生相关性：人类胎儿生长异常每年花费数十亿美元用于新生儿重症监护以及因残疾而产生的后续医疗和社会费用。该项目旨在发现专门进化来保护子宫内婴儿免受胎盘氧气不足后果的胎盘基因。这将为我们提供临床测试的开发地图，以检测子宫内婴儿何时生长不正常，并设计治疗方法以改善其生长和长期健康。