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The Role of Placental Maternal Vascular Underperfusion in Neonatal Pulmonary Hypertension

胎盘母体血管灌注不足在新生儿肺动脉高压中的作用

基本信息

批准号：
10553893
负责人：
Karen K Mestan
金额：
$ 51.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10553893
关键词：
Adult Affect Age-Months Air Angiogenic Factor Biological Assay Biological Markers Birth Birth Weight Blood Vessels Blood specimen Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Bronchopulmonary Dysplasia CD14 gene Cardiopulmonary Chemotaxis Chronic Complex Coupled Cryopreservation Data Defect Depressed mood Development Early identification Ensure Exposure to FCGR3B gene Fetal Growth Retardation Fetal Liver Flow Cytometry Fluorescence-Activated Cell Sorting Gene Expression Gene Targeting Genes Goals Granulocyte Colony-Stimulating Factor Granulocyte-Macrophage Colony-Stimulating Factor Histologic Hospitalization Human Hyperoxia Hypoxia Infant Knock-in Lung Measures Mediating Metabolic Mus Neonatal Newborn Infant Oxygen PGF gene Pathway interactions Patients Perinatal Phenotype Play Pre-Eclampsia Premature Infant Prevention Prevention strategy Preventive treatment Proxy Pulmonary Hypertension Pulmonary vessels Quantitative Reverse Transcriptase PCR Recovery Recurrence Reporting Research Resources Right Ventricular Hypertrophy Risk Role Specimen Survivors Systolic Pressure Testing Therapeutic Time Transplantation Umbilical Cord Blood Umbilical Cord Blood Transplantation VEGFA gene Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Ventricular Work angiogenesis cohort cytokine density differential expression early detection biomarkers effective therapy fetal fetus hypoxia humanized mouse implantation indexing insight lung development lung histology migration monocyte mortality risk neonatal pulmonary hypertension novel peripheral blood predictive marker prenatal exposure prevent protein expression pulmonary arterial pressure receptor response stem cells therapeutic target trophoblast

项目摘要

PROJECT SUMMARY Neonatal pulmonary hypertension (PH) is a serious condition that affects up to one third of premature infants with bronchopulmonary dysplasia (BPD). This entity, known as BPD-associated PH (BPD-PH), is fully established by 1-3 months of age and incurs a four-fold increased risk of death. Survivors of BPD-PH have prolonged and recurrent hospitalizations, and are at risk for chronic cardiopulmonary and metabolic problems. We are committed to developing targeted strategies to prevent BPD-PH in premature infants. Two promising therapeutic targets are the histologic marker, placental maternal vascular underperfusion (MVU) and the intermediate cord blood-derived fetal monocytes (iMNC) that circulate at birth. Our central hypothesis is that fetal iMNCs are adversely programmed by the chronic fetal hypoxia of placental MVU, and contribute to early delayed lung angiogenesis leading to BPD-PH. In Aim #1, we will elucidate the mechanism by which MVU leads to delayed neonatal angiogenesis. Using fetal growth restriction (FGR, birth weight <5th percentile) as the proxy for chronic fetal hypoxia, we will compare iMNC VEGFR1 expression via flow cytometric analysis of 100 cord blood samples from the following groups of infants: 1) preterm MVU with FGR; 2) preterm MVU without FGR; 3) preterm no MVU with FGR; 4) preterm no MVU no FGR (preterm control); 5) term no MVU no FGR (term control). In isolated iMNCs, we will use PCR Array to compare the gene expression profiles of these groups and identify novel gene targets and pathways driven by MVU. In Aim #2 we will identify the perinatal mechanisms by which MVU-exposed fetal iMNCs contribute to delayed neonatal lung angiogenesis: In cultured iMNCs exposed to experimental hypoxia and hyperoxia, we will evaluate VEGFA and VEGFR1 gene and protein expression. We will perform chemotaxis assays to compare iMNC migration in response to exogenous treatment with placental growth factor (PIGF) and granulocyte colony stimulating factor (GCSF), and we will compare iMNC expression of VEGFR1 in bronchoalveolar lavage fluids from intubated preterm infants. Lastly, in Aim #3 we will transplant iMNCs from the 5 patient groups into newborn human GM-CSF knock-in (humanized) mice, and follow the lung histology and PH parameters after chronic hyperoxia exposure (85% oxygen x 14 days). We will test the hypothesis that transplantation of cord blood-derived iMNCs from non-MVU, non-FGR infants (controls) will aid in the prevention of BPD-PH.

项目摘要新生儿肺动脉高压（PH）是一种严重的疾病，影响多达三分之一的早产儿支气管肺发育不良（BPD）。这个实体，被称为BPD-associated PH（BPD-PH），完全在1-3个月大时发病，死亡风险增加四倍。BPD-PH的幸存者长期和反复住院，并有慢性心肺和代谢问题的风险。我们致力于制定有针对性的策略，以预防早产儿的BPD-PH。两个有希望的治疗靶点是组织学标志物，胎盘母体血管灌注不足（MVU）和在出生时循环的中间脐带血来源的胎儿单核细胞（iMNC）。我们的核心假设是胎儿 iMNCs被胎盘MVU的慢性胎儿缺氧不利地编程，并有助于早期延迟的MVU。肺血管生成导致BPD-PH。在目标#1中，我们将阐明MVU导致BPD-PH的机制，新生儿血管生成延迟。使用胎儿生长受限（FGR，出生体重<第5百分位数）作为慢性胎儿缺氧，我们将通过流式细胞术分析100例脐带血iMNC VEGFR 1表达，来自以下婴儿组的样品：1）具有FGR的早产MVU; 2）不具有FGR的早产MVU; 3）具有FGR的早产MVU。无MVU伴FGR; 4）早产儿无MVU无FGR（早产儿对照）; 5）足月儿无MVU无FGR（足月儿对照）。在分离的iMNCs，我们将使用PCR阵列比较这些组的基因表达谱，由MVU驱动的新基因靶点和途径。在目标#2中，我们将确定围产期机制， MVU暴露的胎儿iMNC有助于延迟新生儿肺血管生成：在暴露于MVU的培养iMNC中，实验性低氧和高氧，我们将评估VEGFA和VEGFR 1基因和蛋白表达。我们将进行趋化性试验，以比较iMNC迁移对胎盘外源性治疗的反应。生长因子（PlGF）和粒细胞集落刺激因子（GCSF），我们将比较iMNC表达气管插管早产儿支气管肺泡灌洗液中VEGFR 1的表达。最后，在目标#3中，我们将移植将来自5个患者组的iMNC植入新生人GM-CSF敲入（人源化）小鼠中，并追踪肺慢性高氧暴露后的组织学和PH参数（85%氧气x 14天）。我们将测试假设来自非MVU、非FGR婴儿（对照）的脐带血衍生的iMNC的移植将有助于预防BPD-PH。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The impact of placental pathology discordance in multiple gestation pregnancies on bronchopulmonary dysplasia-associated pulmonary hypertension.

多胎妊娠胎盘病理不一致对支气管肺发育不良相关肺动脉高压的影响。

DOI：
10.1177/2045894020910674
发表时间：
2020
期刊：
Pulmonary circulation
影响因子：
2.6
作者：
Franklin,Andrew;Yallapragada,Sushmita;Birkett,Robert;Grobman,William;Ernst,LindaM;Mestan,Karen
通讯作者：
Mestan,Karen

Umbilical cord miRNAs to predict neonatal early onset sepsis.