权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Optimizing Therapeutic delivery of MicroRNAs to prevent chronic lung disease in Preterm infants.

优化 MicroRNA 的治疗递送以预防早产儿慢性肺部疾病。

基本信息

批准号：
10065005
负责人：
Lynette Kay Rogers
金额：
$ 30.94万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-10 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065005
关键词：
Adult Affect Age Alveolar Alveolar wall Attenuated Autopsy Birth Blood Banks Blood specimen Bronchopulmonary Dysplasia Characteristics Child Childhood Chronic lung disease Chronically Ill Clinical Clinical Data Clinical Research Consumption Data Defect Dependovirus Deposition Development Diffuse Disease Dose Drug Delivery Systems Elements Engineering Epigenetic Process Event Exposure to Fibrosis Future Gestational Age Growth Growth and Development function Human Hyperoxia Incidence Infant Infection Inflammation Intervention Intranasal Administration Lead Life Cycle Stages Life Expectancy Link Lipids Liposomes Lung Lung diseases Mechanical ventilation Mediating MicroRNAs Morbidity - disease rate Mus Neonatal Neonatal Hyperoxic Injury Neonatal Intensive Care Newborn Infant Organ Outcome Oxygen Oxygen Therapy Care Pathology Pathway interactions Perinatal Phenotype Plasma Play Population Premature Infant Process Pulmonary Pathology Pulmonary function tests Resources Risk Role Sampling Signal Pathway Structure of parenchyma of lung Suspensions Testing Therapeutic Therapeutic Intervention Time Translating Umbilical Cord Blood antenatal base biobank clinical phenotype clinically relevant disorder prevention effective intervention experimental study improved in utero innovation interstitial lung development mortality mouse model nanoparticle neonatal care novel novel therapeutic intervention novel therapeutics offspring particle postnatal prenatal exposure preterm newborn prevent programs pup repaired repository respiratory response restoration surfactant theranostics therapeutic evaluation therapeutic miRNA therapeutically effective vector

项目摘要

Abstract Chronic lung disease (CLD) represents an important cause of morbidity and mortality in preterm infants. Although advances in neonatal care have decreased the incidence of chronic lung disease in preterm infants, a subset of these infants remain dramatically affected, developing “severe” lung pathologies along with other organ associated complications. Currently, few clinically useful strategies have been developed to identify and treat the infants at greatest risk. We hypothesize that the severe pulmonary disease in preterm infants is a result of epigenetic changes caused by events in utero which primes them for exacerbated responses to interventions after birth. MicroRNAs (miRs) are epigenetic regulators involved in growth, development, and repair processes, however dysregulation of miRs are associated with pulmonary disease. We have identified a microRNA, miR-29b, that is suppressed at birth in preterm infants that go on to develop chronic lung disease. The central hypothesis of this proposal is that restoration of pulmonary expression of microRNA-29b will attenuate morbidites associated with newborn chronic lung disease. To test our hypothesis, we will use our extensively characterized murine model; systemic maternal LPS followed by exposure of the pups to hyperoxia for 14 days. The objective of this proposal is to test novel therapeutic strategies to reverse epigenetic changes resulting from exposure to perinatal inflammation. To accomplish this we propose three Aims: Aim 1 will test the hypothesis that AAV9-mediated delivery of miR-29b to newborn mouse pups will rescue the phenotype caused by perinatal inflammation and neonatal hyperoxia. To test this hypothesis, we will build upon our preliminary data using an innovative delivery strategy, adeno-associated virus, to restore the pulmonary expression of miR-29b which plays an essential role in lung development and fundamental signaling pathways. Aim 2 will test the hypothesis that miR-29b can be efficiently delivered to the lungs of a newborn mouse using lipid-based vehicles. We will investigate relevant alternative delivery strategies including liposomal nanoparticles and surfactant suspension that could be directly translated into therapies for infants. Aim 3 will utilize bio-banked blood specimens obtained at delivery and at 36 weeks' corrected age to define the clinical characteristics of infants with decreased miR29b expression at birth and at the time of clinical determination of BPD status. Using existing biorespositories, we will investigate cord blood and infant samples for associations between clinical variables and neonatal miR expression to optimize identification of the population of infants that would most benefit from miR therapies. In summary, these studies will provide the framework for new and novel therapeutic approaches that include delivery of miRs to prevent pulmonary morbidities in newborn infants.

抽象的慢性肺病（CLD）是早产儿发病和死亡的重要原因。尽管新生儿护理的进步降低了早产儿慢性肺病的发病率，但这些婴儿中的一部分仍然受到严重影响，出现“严重”肺部病变以及其他疾病器官相关并发症。目前，几乎没有开发出临床上有用的策略来识别并治疗风险最大的婴儿。我们假设早产儿的严重肺部疾病是子宫内事件引起的表观遗传变化的结果，这些变化使它们对外界的反应加剧出生后的干预。 MicroRNA (miR) 是参与生长、发育和发育的表观遗传调节因子然而，miR 的失调与肺部疾病有关。我们已经确定一种 microRNA，miR-29b，在早产儿出生时受到抑制，随后发展成慢性肺病疾病。该提案的中心假设是恢复肺部表达 microRNA-29b 将减轻与新生儿慢性肺病相关的疾病。来测试我们的假设，我们将使用我们广泛表征的小鼠模型；全身母体 LPS，然后让幼崽暴露在高氧环境中 14 天。该提案的目的是测试新的治疗方法逆转因暴露于围产期炎症而导致的表观遗传变化的策略。为了实现这一点我们提出三个目标：目标 1 将测试 AAV9 介导的 miR-29b 递送至新生小鼠幼崽将挽救围产期炎症和新生儿引起的表型高氧。为了检验这个假设，我们将使用创新的交付方式建立我们的初步数据策略，腺相关病毒，恢复 miR-29b 的肺部表达，其发挥着重要作用肺部发育和基本信号传导途径。目标 2 将检验 miR-29b 可以使用基于脂质的载体将其有效地输送到新生小鼠的肺部。我们将调查相关的替代递送策略，包括脂质体纳米颗粒和表面活性剂悬浮液，可以直接转化为婴儿疗法。目标 3 将利用生物库中获得的血液样本分娩时和 36 周校正年龄时，以确定婴儿体重下降的临床特征出生时和临床确定 BPD 状态时的 miR29b 表达。使用现有的生物储存库，我们将研究脐带血和婴儿样本以了解临床变量之间的关联和新生儿 miR 表达，以优化识别最能受益的婴儿群体 miR疗法。总之，这些研究将为新的治疗方法提供框架包括递送 miR 来预防新生儿肺部疾病的方法。