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

• 批准号: 8137051
• 负责人: VIRENDER K REHAN
• 金额: $ 40.17万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8137051
• 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

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）：怀孕期间的孕产妇吸烟会对胎儿发育中的肺产生广泛的影响，从而极大地损害了其长期功能和能力。这些作用背后的分子机制尚不清楚。由于正常的肺发育和损伤/修复都使用常见的肺泡上皮 - 间质信号传导途径来维持稳态，因此我们建议在子宫内尼古丁的暴露破坏了关键的关键的上皮 - 层分泌旁分泌信号通路，导致肺泡层层间层间菌菌（Aifbro）（aifbrosial fibroslasts）（aifbro）（aifbro）（aifbro）（aif）致肌纤维细胞（myfs）。这种AIF至MYF转分化的特征是向下调节过氧化物酶体增殖物激活受体伽马（PPAR（PPAR（）信号通路途径，并加强无翼/INT（WNT）信号通路的调节。最近已经描述了信号传导，没有关于其对发育肺部Wnt信号的影响的信息。向上调节PPAR（在子宫内尼古丁诱导的肺损伤中，信号传导可以预防甚至逆转。使用良好的体外和体内模型，尼古丁尼古丁诱导的肺损伤，通过实时RT- PCR，西方分析，西方分析，免疫组织化学，激光捕获显微解剖，代谢组学，反义和过度表达研究以及体内肺功能测试，我们将确定（1）在子宫内尼古丁暴露中，如何改变肺发育，导致结构和功能的变化，以及（如果PPAR）（2）（如果PPAR）（2）激动剂和/或Wnt拮抗剂，无论是单独或组合，都可以预防和/或反向围产期尼古丁暴露诱导的PPAR的改变（以及肺间隙中的Wnt信号传导，因此肺结构和功能。由于我们使用的范式和模型是基于肺泡性抗体的形成，建立和稳态的通用发展模型，因此所产生的信息不仅限于子宫内尼古丁诱导的损伤，但可能会有很多通常，对肺发育和损伤/修复的适用性更大。因此，通过利用功能性基因组学，本文提出的研究可能会转化为所有慢性肺部疾病的新型和创新的预防和治疗方法。项目叙述：怀孕期间的孕产妇不仅在妊娠和直接新生儿时期构成了重大风险，而且还可能导致寿命长期的医疗并发症，包括毁灭性呼吸系统问题。孕产妇吸烟对肺部的有害作用的基础机制是复杂的，尚不完全理解。拟议的研究使用新颖和创新的概念以及最先进的技术，将揭示不仅是子宫烟雾暴露引起的肺损伤的机制，而且几乎所有其他形式的慢性肺疾病。