A Molecular Approach to Prevent Pulmonary Dysfunction in the Intrauterine Growth

预防宫内生长过程中肺功能障碍的分子方法

基本信息

批准号：
7936249
负责人：
VIRENDER K REHAN
金额：
$ 6.85万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-20 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7936249
关键词：
Accounting Adolescent Adult Affect Age Alveolar Alveolus Arts Cells Chronic lung disease Data Development Diabetes Mellitus Epidemiology Epithelial Fetal Growth Fetal Growth Retardation Functional disorder Genes Growth Homeostasis Human Hypertension Immunohistochemistry Infant Intervention Life Lung Mediating Mesenchymal Modeling Molecular Morbidity - disease rate Nutrient Obesity Organ PPAR gamma Pathogenesis Pathway interactions Peroxisome Proliferator-Activated Receptors Phospholipids Pregnancy Prevention Preventive Proteins Pulmonary function tests Rattus Regulator Genes Risk Rodent Model Secondary to Signal Pathway Signal Transduction Staging Stress Structure Techniques Technology Therapeutic Time Translating base design fetal food restriction functional genomics in vivo innovation laser capture microdissection lung development morphometry neonate novel offspring overexpression parathyroid hormone-related protein postnatal prevent programs public health relevance respiratory response surfactant

项目摘要

DESCRIPTION (provided by applicant): Intrauterine growth restriction (IUGR) alters lung development, increasing the risk of respiratory compromise throughout postnatal life. Vertical integration of the cell-molecular mechanism(s) underlying this respiratory compromise offers a powerful functional genomic approach to understand the pathogenesis of chronic lung disease in the IUGR offspring. Since lung development is determined by spatio-temporally specific alveolar epithelial-mesenchymal interactions, we hypothesize that IUGR alters the key alveolar epithelial-mesenchymal signaling pathways that are essential for normal lung development. We propose utilizing a well established rodent model of 50% maternal food restriction (MFR) from day 10 of gestation to term and through postnatal day 21. This model has previously been shown to demonstrate adult-onset obesity, diabetes, and hypertension in the MFR offspring. Now our preliminary data provide clear evidence for failed alveolarization and pulmonary dysfunction in the MFR offspring. Using this model and well established molecular techniques such as lung morphometry, Real-Time-PCR, Western analysis, immunohistochemistry, laser capture microdissection, anti-sense and overexpression studies, and in vivo pulmonary function testing, we will 1) determine the effect of MFR on lung structure and function in the offspring at postnatal days 1 and 21, and months 3 and 9; 2) specifically examine how MFR affects alveolar Parathyroid Hormone-related Protein/Peroxisome Proliferator-Activated Receptor 3 signaling that is known to be essential for normal lung development; and 3) evaluate if alterations in key alveolar epithelial-mesenchymal signaling pathways affected by MFR, and the subsequent lung structural and functional changes, can be normalized by either over-expression or silencing of the key regulatory genes involved. Based on our preliminary data, we expect that, in the lung of the MFR offspring, we will find disruption in molecular pathways that are essential for alveolarization, accounting for the altered lung programming seen in the offspring, hence offering the possibility of prevention and/or reversal of such changes with specific molecular interventions. By exploiting the functional genomic approach, the studies proposed herein will translate into novel and innovative molecular preventive and therapeutic approaches for pulmonary dysfunction seen in IUGR offspring secondary to not only MFR, but also to other causes. PUBLIC HEALTH RELEVANCE: There is accumulating evidence to show that infants who are delivered following growth restriction during the fetal period have significant lung morbidity during their postnatal life. Further, since the mechanism of this lung morbidity is not known, there is no specific intervention to prevent it. Using a well established rat model of intrauterine growth restriction and the state-of-the-art technology, we propose studies that will unravel the fundamental molecular mechanism (s) of pulmonary dysfunction in the growth restricted offspring, allowing us to design novel intervention strategies that may not only prevent, but also reverse intrauterine growth restriction associated lung damage during postnatal life.

描述（由申请人提供）：宫内生长限制（IUGR）改变了肺发育，增加了整个产后生命的呼吸妥协的风险。这种呼吸折衷的细胞分子机制（S）的垂直整合提供了一种强大的功能基因组方法，可以理解IUGR后代慢性肺部疾病的发病机理。由于肺发育是通过时空特异性肺泡上皮 - 间质相互作用确定的，因此我们假设IUGR改变了对正常肺发育至关重要的关键肺泡上皮 - 间质信号通路。我们建议利用从妊娠10到学期到期间和到产后21的50％母体食品限制（MFR）的良好啮齿动物模型。此前已证明该模型在MFR中证明了成人发作的肥胖，糖尿病和高血压后代。现在，我们的初步数据为MFR后代的肺泡化和肺部功能障碍提供了明确的证据。使用该模型和良好建立的分子技术，例如肺形态计量学，实时PCR，西方分析，免疫组织化学，激光捕获微解剖，抗渗透和过表达研究以及体内肺功能测试，我们将确定1）确定1）确定MFR在产后第1和21天的后代中的肺结构和功能，以及第3和9个月； 2）特别检查MFR如何影响肺泡甲状旁腺激素相关的蛋白/过氧化物酶体增殖物激活的受体3信号传导，这对于正常的肺发育至关重要； 3）评估受MFR影响的关键肺泡上皮 - 间充质信号通路的改变以及随后的肺结构和功能变化，可以通过过表达或对所涉及的关键调节基因的沉默来归一化。根据我们的初步数据，我们希望在MFR后代的肺中，我们会发现分子途径中的中断，这对于肺泡化至关重要，这是对后代所看到的改变的肺编程的构成，因此提供了预防和//////可能的可能性。或通过特定分子干预措施逆转这种变化。通过利用功能性基因组方法，本文提出的研究将转化为新的和创新的分子预防和治疗方法，用于在IUGR后代中不仅是MFR，而且还涉及其他原因。公共卫生相关性：有积累的证据表明，在胎儿期间生长限制后接受的婴儿在产后生命中具有明显的肺部发病率。此外，由于尚不清楚这种肺发病率的机制，因此没有具体的干预措施来预防它。我们使用宫内生长限制和最先进技术的大鼠模型，我们提出的研究将在生长受限的后代中揭示肺功能障碍的基本分子机制，从而使我们能够设计新的干预策略这可能不仅可以预防，而且还会反向宫内生长限制，与产后生活期间的肺部损害有关。