Fibroblast Cell Signaling in Utero Nicotine-Induced Lung Injury

子宫内尼古丁引起的肺损伤中的成纤维细胞信号传导

基本信息

批准号：
8309208
负责人：
VIRENDER K REHAN
金额：
$ 26.97万
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：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309208
关键词：
Acinus organ component Agonist Alveolar Chronic lung disease Complex Development Down-Regulation Epithelial Exposure to Fetus Fibroblasts Homeostasis Immunohistochemistry In Vitro Injury Life Lung Mesenchymal Mesenchyme Modeling Molecular Molecular Target Myofibroblast Newborn Infant Nicotine PPAR gamma Paracrine Communication Pathway interactions Perinatal Perinatal Exposure Peroxisome Proliferator-Activated Receptors Phenotype Pregnancy Preventive Pulmonary function tests Reverse Transcriptase Polymerase Chain Reaction Risk Signal Pathway Signal Transduction Smoke Structure Technology Testing Therapeutic Time Translating Up-Regulation Work alveolar homeostasis base functional genomics in utero in vivo in vivo Model injury and repair innovation interstitial laser capture microdissection lung development lung injury maternal cigarette smoking medical complication metabolomics novel parathyroid hormone-related protein prevent respiratory transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): Maternal smoking during pregnancy causes a broad range of effects on the developing lung of the fetus that greatly impairs its long-term function and capacity. The molecular mechanisms underlying these effects are not known. Since both normal lung development and injury/repair utilize common alveolar epithelial-mesenchymal signaling pathways to maintain homeostasis, we propose that in utero nicotine exposure disrupts the critical homeostatic epithelial-mesenchymal paracrine signaling pathways, resulting in the transdifferentiation of alveolar intersitial fibroblasts (AIFs) to myofibroblasts (MYFs). This AIF-to-MYF transdifferentiation is characterized by down regulation of the Peroxisome Proliferator Activated Receptor gamma (PPAR() signaling pathway and up regulation of the Wingless/Int (Wnt) signaling pathway. Although the effects of in utero nicotine exposure on PPAR( signaling have recently been described, there is no information on its effect on the Wnt signaling in the developing lung. We hypothesize that in utero nicotine exposure up-regulates AIF Wnt signaling and that by specific molecular targeting to down regulate the Wnt signaling and/or up regulate the PPAR( signaling, in utero nicotine-induced lung injury can be prevented or even reversed. Using well established in vitro and in vivo models of in utero nicotine-induced lung injury, through real-time RT- PCR, Western analysis, immunohistochemistry, laser capture microdissection, metabolomics, antisense and over expression studies, and in vivo pulmonary function tests, we will determine (1) how in utero nicotine exposure alters lung development, resulting in altered structure and function, and (2) if PPAR( agonists and/or Wnt antagonists, either alone or in combination, can prevent and/or reverse perinatal nicotine exposure-induced alterations in PPAR( and Wnt signaling in lung mesenchyme, and hence lung structure and function. Since the paradigm and models used by us are based on a universal developmental model for the formation, establishment, and homeostasis of the alveolar acinus, the information generated will not be limited only to in utero nicotine-induced injury but is likely to have a much larger applicability to lung development and injury/repair in general. Therefore, by utilizing functional genomics, the studies proposed herein are likely to translate into novel and innovative molecular preventive and therapeutic approaches for all chronic lung diseases in general. PROJECT NARRATIVE: Maternal smoking during pregnancy poses significant risks not only during gestation and immediate newborn period, but may also results in life long medical complications including devastating respiratory problems. The mechanisms underlying the harmful effects of maternal smoking on the lung are complex and incompletely understood. Using novel and innovative concepts, and the state-of-the-art technology, the proposed studies will unravel mechanisms that underlie not only the in utero smoke exposure-induced lung injury, but also almost all other forms of chronic lung diseases.

描述（由申请人提供）：母亲在怀孕期间吸烟会对胎儿的肺部发育产生广泛的影响，极大地损害其长期功能和容量。这些效应背后的分子机制尚不清楚。由于正常的肺发育和损伤/修复都利用共同的肺泡上皮间质信号通路来维持体内平衡，因此我们认为子宫内尼古丁暴露会破坏关键的稳态上皮间质旁分泌信号通路，导致肺泡间质成纤维细胞（AIF）的转分化肌成纤维细胞（MYF）。这种 AIF 至 MYF 转分化的特点是过氧化物酶体增殖物激活受体 γ (PPAR() 信号通路的下调和 Wingless/Int (Wnt) 信号通路的上调。虽然子宫内尼古丁暴露对 PPAR() 的影响最近描述了 AIF 信号传导，但尚无关于其对发育中肺部 Wnt 信号传导影响的信息，我们假设子宫内尼古丁暴露会上调 AIF。 Wnt 信号传导以及通过特定分子靶向下调 Wnt 信号传导和/或上调 PPAR( 信号传导)，可以预防甚至逆转子宫内尼古丁引起的肺损伤。使用成熟的体外和体内子宫内模型尼古丁引起的肺损伤，通过实时RT-PCR、Western分析、免疫组织化学、激光捕获显微切割、代谢组学、反义和过表达研究以及体内肺功能测试，我们将确定（1）如何子宫内尼古丁暴露会改变肺部发育，导致结构和功能改变；(2) PPAR( 激动剂和/或 Wnt 拮抗剂，单独或联合使用) 是否可以预防和/或逆转围产期尼古丁暴露引起的 PPAR( 和肺间质中的 Wnt 信号传导，进而影响肺的结构和功能。由于我们使用的范式和模型基于肺泡腺泡形成、建立和稳态的通用发育模型，因此生成的信息将不仅限于子宫内尼古丁引起的损伤，而且可能有更多的信息。一般来说，对肺部发育和损伤/修复有更大的适用性。因此，通过利用功能基因组学，本文提出的研究可能转化为针对所有慢性肺病的新颖和创新的分子预防和治疗方法。项目叙述：母亲在怀孕期间吸烟不仅会在妊娠期和新生儿期带来重大风险，而且还可能导致终生的医疗并发症，包括毁灭性的呼吸系统问题。母亲吸烟对肺部有害影响的机制很复杂且尚未完全了解。利用新颖和创新的概念以及最先进的技术，拟议的研究将揭示不仅是子宫内烟雾暴露引起的肺损伤的机制，而且还揭示几乎所有其他形式的慢性肺病的机制。