Hypoxia Signaling and Spontaneous Pulmonary Fibrosis in a Novel Mouse Model

新型小鼠模型中的缺氧信号传导和自发性肺纤维化

• 批准号: 8824228
• 负责人: Vrushank Dave
• 金额: $ 23.81万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824228
• 关键词: Accounting; Affect; Age; Aging; Alveolar; American; Animal Model; Appearance; Automobile Driving; Binding; CXCR4 gene; Cell Hypoxia; Cells; Cellular Stress; Cessation of life; Chronic; Clinic; Clinical; Collagen; Communities; Data; Deposition; Detection; Development; Diagnostic; Disease; Disease Progression; Edema; Elderly; Epithelial; Epithelial Cells; Epithelium; Event; Exhibits; Experimental Models; Fibroblasts; Fibrosis; Genes; Genetic Models; Goals; HIF1A gene; Hamman-Rich syndrome; Health; Human; Hypoxia; In Vitro; Incidence; Individual; Inflammation; Injury; Knowledge; Lung; Lung diseases; Mediating; Membrane; Mesenchymal; Modeling; Molecular; Mus; Nature; Organ; Outcome; Oxygen measurement, partial pressure, arterial; Pathogenesis; Pathway interactions; Patients; Perfusion; Phenotype; Population; Prevalence; Public Health; Pulmonary Fibrosis; Regulation; Respiratory System; Respiratory physiology; Role; Signal Transduction; Signaling Molecule; Stress; Stromal Cell-Derived Factor 1; Structure; Systems Biology; Testing; Therapeutic; Therapeutic Intervention; Time; Transforming Growth Factor beta; VHL gene; Von Hippel-Lindau Syndrome; aged; base; beta catenin; cell type; cytokine; defined contribution; effective therapy; in vivo; insight; killings; lung hypoxia; lung injury; molecular pathology; mortality; mouse model; novel; paracrine; preclinical study; prevent; prognostic; repaired; respiratory; response; targeted treatment; tool

DESCRIPTION (provided by applicant): Idiopathic PF (IPF) is a lethal, incurable disease killing 40,000 Americans every year. As the aged population has grown, the prevalence of IPF has jumped from 20 to 30 cases/100,000 individuals. Despite this enormous public health burden, the molecular basis of the origins and progressive nature of IPF remains elusive. Continuation of this knowledge gap has stymied the development of targeted therapies for IPF. Thus, the long-term goal is to define molecules, mechanisms and cell types in the lung that contribute to the initiation and progression of IPF that will aid in the development of targeted therapies for IPF. While mechanistic insights are being generated from current animal models of injury-induced fibrosis, these models remain inherently limited as the fibrosis resolves over time, precluding the identification of molecular drivers participating in the progression of PF. Therefore, the objective of the present project is to fill this significant gap by developing, characterizing and refining a mouse model of PF exhibiting progressive nature of the disease, recapitulating some of the clinico-pathological features of IPF. Repeated injury to the respiratory epithelial cells (RECs) causes cellular stress, triggering aberrant epithelial repair associated with molecular alterations that render RECs profibrotic. These RECs secrete fibrogenic signals, activating resident fibroblasts/mesenchymal cells, contributing to fibrosis. One such epithelial stress factor is chronic hypoxic response to the epithelial cells, which is known to alter structure and function of RECs in vitro. In addition, based on our in vivo data presented here, we will test the central hypothesis that aberrant hypoxic responses originating in the lung epithelium render RECs profibrotic, contributing to PF in vivo. We will delineate molecules/mechanisms initiating PF utilizing a mouse model of spontaneous and progressive PF that slowly develops over 3 months due to chronic hypoxia signaling elicited by deletion of Vhl gene in the conducting and alveolar airway epithelial cells (AECs) in vivo. This model correlates well with slow progressive features of fibrosis seen in IPF patients in the clinic. We show that hypoxic response in the RECs in vivo triggers activation of Wnt/ß-catenin, TGF-ß and CXCR4/SDF-1 signaling, consistent with their role in PF and findings in IPF patients. Aim#1 will define earliest molecular events initiating PF and molecules activating Wnt/ß-catenin and TGF-pathways in the RECs using systems biology approaches. Aim #2 will ascertain the regulation of CXCR4/SDF-1 genes in human RECs and examine the paracrine roles of profibrotic RECs in activating fibrogenic phenotype of primary human parenchymal fibroblasts. The outcome of the project will be significant, revealing molecules/mechanisms defining early molecular events driving PF. The molecules and signaling networks identified in the profibrotic epithelia would have high prognostic, diagnostic and therapeutic utility. The characterized mouse model holds immense potential for pre-clinical studies in building clinical rationale for emerging targeted therapies of IPF.

特发性肺纤维化（IPF）是一种致命的、无法治愈的疾病，每年有40，000名美国人死亡。随着老年人口的增长，IPF的患病率从20例/100，000例跃升至30例/100，000例。尽管有这种巨大的公共卫生负担，但IPF起源和进展性质的分子基础仍然难以捉摸。这种知识差距的持续阻碍了IPF靶向治疗的开发。因此，长期目标是确定肺中有助于IPF发生和进展的分子、机制和细胞类型，这将有助于开发IPF的靶向治疗。虽然从目前损伤诱导的纤维化的动物模型中产生了机制性见解，但这些模型随着纤维化随着时间的推移而消退， 因此，本项目的目的是通过开发、表征和改进表现出疾病进行性的PF小鼠模型，重现IPF的一些临床病理学特征，来填补这一重大空白。 呼吸道上皮细胞（RECs）的反复损伤会导致细胞应激，引发与分子改变相关的异常上皮修复，使RECs发生促纤维化。这些REC分泌纤维化信号，激活驻留的成纤维细胞/间充质细胞，促进纤维化。一种这样的上皮应激因子是对上皮细胞的慢性缺氧反应，已知其在体外改变REC的结构和功能。此外，根据我们在这里提出的体内数据，我们将测试的中心假设，即异常缺氧反应起源于肺上皮细胞呈现REC促纤维化，促成PF在体内。我们将描述分子/机制，启动PF利用小鼠模型的自发性和进行性PF，缓慢发展超过3个月，由于慢性缺氧信号引起的Vhl基因的缺失，在传导和肺泡气道上皮细胞（AEC）在体内。该模型与临床上IPF患者中观察到的纤维化缓慢进展特征相关性良好。我们发现，体内REC中的缺氧反应触发了Wnt/β-连环蛋白、TGF-β和CXCR 4/SDF-1信号传导的激活，这与它们在PF中的作用和IPF患者中的发现一致。目标#1将使用系统生物学方法定义启动PF的最早分子事件以及激活REC中Wnt/Beta-连环蛋白和TGF-途径的分子。目的#2将确定CXCR 4/SDF-1基因在人REC中的调节，并检查促纤维化REC在激活原代人实质成纤维细胞的纤维发生表型中的旁分泌作用。该项目的结果将是显著的，揭示了定义驱动PF的早期分子事件的分子/机制。在促纤维化上皮中鉴定的分子和信号网络将具有较高的预后、诊断和治疗效用。表征的小鼠模型具有巨大的临床前研究潜力，可为IPF的新兴靶向治疗建立临床依据。