Nrf2 and Radiation-induced pulmonary fibrosis.

Nrf2 和辐射诱导的肺纤维化。

• 批准号: 8606883
• 负责人: MICHAEL L. FREEMAN
• 金额: $ 42.92万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606883
• 关键词: Address; Adverse effects; Affect; Alveolar; Bioinformatics; Bleomycin; Bone Marrow; CCL3 gene; CCR1 gene; Cancer Survivor; Cells; Cessation of life; ChIP-seq; Chest; Chimera organism; Collagen; Complex; Data; Development; Dose-Limiting; Epithelial; Erythroid; Event; Exhibits; Fibroblasts; Fibrosis; Genes; Genetic; Genetic Engineering; Genetic Transcription; Goals; Human; Injury; Knockout Mice; Knowledge; Late Effects; Life; Link; Lung; Lung diseases; Lysophospholipids; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Myofibroblast; Normal tissue morphology; Nuclear; Outcome; Oxidative Stress; Pathway interactions; Patients; Phenotype; Plasminogen Activator Inhibitor 1; Predisposition; Production; Proteins; Publishing; Pulmonary Fibrosis; Radiation; Radiation therapy; Reporter; Repression; Research; Risk; S100A8 gene; Signal Transduction; Site; Technology; Testing; Therapeutic; Time; Type II Epithelial Receptor Cell; Wild Type Mouse; Work; base; connective tissue growth factor; in vivo; insight; irradiation; lung injury; lysophosphatidic acid; mortality; mouse model; novel; novel therapeutics; prevent; promoter; public health relevance; transcription factor

DESCRIPTION (provided by applicant): Radiation-induced pulmonary fibrosis (RiPF) is a 'late normal tissue lung injury' initiated by radiation therapy and can result in significant morbidity ad mortality among cancer survivors. Although progress has been made toward identifying pathophysiological events that give rise to RiPF, there is a substantial gap in knowledge regarding the molecular under-pinnings responsible for this radiation-induced late effect. Our long- term goal is to identify factors that regulate RiPF susceptibility and elucidate their molecular mechanisms in order to ultimately devise therapeutic strategies for preventing and/or mitigating RiPF. The objective of this application is to provide a mechanistic link between factors that regulate TGF-¿1/Smad3 signaling and RiPF. Our central hypothesis is that the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a critical molecule for regulating TGF ¿-mediated RiPF and this is based on our preliminary and published data. Three aims will be used to test this hypothesis. Aim 1 will test the working hypothesis that Nrf2 repressesTGF-¿1/Smad3 fibrogenic signaling. This aim will determine if Nrf2-mediated repression of TGF- ¿1/Smad signaling is specific for a subset of profibrotic genes or represents a global mechanism of repression. A ChIP-sequencing/bioinformatics analysis will be used to identify Nrf2-promoter interactions at CAGA sites in TGF-¿1/Smad3-regulated fibrosis-inducing genes in primary pulmonary fibroblast and alveolar epithelial type II (AET II) cells. In vivo experimentation will b used to validate a mechanistic link between Nrf2 and fibrotic TGF-¿ signaling. Aim 2 will determine the origin of myofibroblast recruitment following thoracic irradiation and test whether recruitment is Nrf2 dependent. Fibrotic TGF-¿ signaling involves complex circuitry. Research outlined in this aim focuses on a key pathway: recruitment of collagen/matrix secreting myofibroblasts, self perpetuating cells critical for development of pulmonary fibrosis. Yet their cell-of-origin in RiPF is not well characterized. We will use Cre-lox technology/cell fate reporter mice and bone marrow chimera experimentation to determine the contribution of resident fibroblasts, AET II cells, and bone marrow- derived fibrocytes to myofibroblast formation and whether recruitment is Nrf2 dependent. Aim 3 will test the hypothesis that an Nrf2 deficiency increases the occurrence of radiation-induced life-threatening pulmonary injury. This aim will use genetically engineered Nrf2 mice to address this proof of concept. The goal is to relate a cell-specific Nrf2 deficiency with phenotype. Successful completion of Aim 1 will identify a new paradigm for Nrf2 signaling. Aim 2 will connect Nrf2 signaling with pathophysiological recruitment of myofibroblasts. Aim 3 addresses outcome. These aims have the potential to provide novel mechanistic insights into RiPF, leading eventually to new therapeutic strategies for preventing or mitigating RiPF.

描述（由适用提供）：辐射诱导的肺纤维化（RIPF）是通过放射治疗引发的“晚期正常组织肺损伤”，可导致癌症存活中显着的发病率AD死亡率。尽管在识别引起RIPF的病理生理事件方面取得了进展，但关于导致这种辐射引起的晚期效应的分子不足的小钳的知识存在很大的差距。我们的长期目标是确定调节RIPF敏感性的因素并阐明其分子机制，以最终制定预防和/或缓解RIPF的治疗策略。该应用的目的是提供因素之间的机械联系 调节tgf-€1/smad3信号传导和RIPF。我们的中心假设是转录因子核因子（红细胞来源2）类似2（NRF2）是调节TGF的关键分子 - 介导的RIPF，这是基于我们的初步和发布的数据。将使用三个目标来检验这一假设。 AIM 1将测试NRF2抑制剂1/SMAD3纤维化信号传导的工作假设。该目的将确定TGF-»1/SMAD信号的NRF2介导的表示特定于纤维化基因的子集或代表全局表达机制。将使用CHIP序列/生物信息学分析来鉴定TGF-€1/SMAD3调节纤维化诱导的基因的NRF2促进剂相互作用在原发性肺成纤维细胞和肺泡上皮II型II（AET II）细胞中。体内实验将B将用于验证NRF2和纤维化TGF-信号之间的机械联系。 AIM 2将确定胸腔照射后肌成纤维细胞募集的起源，并测试招募是否取决于NRF2。纤维化的TGF-€信号传导涉及复杂的电路。此目标中概述的研究重点是关键途径：募集胶原蛋白/基质分泌肌纤维细胞，自我永久细胞对于肺纤维化发展至关重要。然而，他们在RIPF中的原始细胞没有很好的特征。我们将使用Cre-Lox技术/牢房命运记者 AIM 3将检验以下假设：NRF2缺乏会增加辐射引起的威胁生命的肺损伤的发生。该目标将使用一般设计的NRF2小鼠来解决此概念证明。目的是将特异性的NRF2缺乏症与表型联系起来。成功完成AIM 1将确定NRF2信号的新范式。 AIM 2将将NRF2信号传导与肌纤维细胞的病理生理募集联系起来。 AIM 3解决结果。这些目标有潜力提供对RIPF的新机械见解，最终导致了预防或减轻RIPF的新治疗策略。