HL-Role of c-Myc in myofibroblast differentiation in pulmonary fibrosis

HL-c-Myc 在肺纤维化肌成纤维细胞分化中的作用

基本信息

批准号：
9449676
负责人：
Stijn Piet Johan De Langhe
金额：
$ 43.77万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-09 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9449676
关键词：
Address Alveolar Applications Grants Architecture Attenuated Back Bleomycin Cell Differentiation process Cells Cicatrix Collagen Collagen Type I Data Deposition Development Diagnosis Disease Epithelial Extracellular Matrix FDA approved Fibroblasts Fibrosis Gene Targeting Genetic Genetic Transcription Goals Hamman-Rich syndrome Human Individual Injury Knowledge Lung Lung diseases Maintenance Mediating Mediator of activation protein Mesenchymal Mesenchymal Differentiation Mesenchyme Modeling Mus Muscle Cells Myofibroblast Nuclear Pathogenesis Pathway interactions Patients Phase Pirfenidone Process Proliferating Pulmonary Fibrosis Reporting Resolution Respiratory physiology Role Signal Transduction Smooth Muscle Actin Staining Method Source Structure of parenchyma of lung Testing Therapeutic Transforming Growth Factor beta WNT Signaling Pathway alveolar epithelium beta catenin c-myc Genes cell type connective tissue growth factor improved indium-bleomycin lung development lung injury novel therapeutics outcome forecast overexpression prevent public health relevance respiratory smooth muscle therapeutic target transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): HL-131: Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive, and ultimately fatal disorder with a poorly understood pathogenesis and no cure. Patients with IPF typically survive 2 to 4 years after diagnosis. IPF is associated with the progressive invasion of the lung parenchyma by activated mesenchymal cells, in particular myofibroblasts, which form `fibroblastic foci' and cause scarring by depositing excessive extracellular matrix resulting in a loss of alveolar architecture. The goal of this proposal is to identify the mesenchymal cell type that gives rise to myofibroblasts and its mechanism of differentiation. Our preliminary studies show that lipofibroblasts are the source for the majority of myofibroblasts after bleomycin injury. In addition, our data indicate that during te resolution phase a subset of myofibroblasts revert back to the lipofibroblast lineage. Our preliminary data also demonstrate that c-Myc, a key Wnt target gene in lung mesenchyme, is strongly expressed in myofibroblasts in lungs after bleomycin injury. Interestingly, our preliminary data also indicate that overexpression of c-Myc by itself (in the absence of lung injury) is sufficient to drive the differentiation and accumulation of myofibroblasts throughout th lung parenchyma. These myofibroblasts are highly proliferative and express high levels of c-Myc, α-Sma and collagen compared to surrounding or wild type mesenchyme. We hypothesize that c-Myc induces lipofibroblast to myofibroblast transdifferentiation and their subsequent proliferation in pulmonary fibrosis. We also hypothesize that c-Myc inactivation in myofibroblasts will promote the resolution of fibrotic lung disease by promoting dedifferentiation of myofibroblasts into non proliferative lipofibroblasts. These hypotheses will be addressed with three specific aims. In specific aim 1 we will test the hypothesis that lipofibroblasts transdifferentiate into myofibroblasts after bleomycin-mediated lung injury and that myofibroblasts dedifferentiate into lipofibroblasts during the resolution of fibrosis in mice. In specific aim 2 we will test the hypothesis that c-Myc is sufficient to transdifferentiate lipofibroblasts into highly proliferative myofibroblasts and to maintain their differentiation stats. Lastly in specific aim 3 we will test the hypothesis that c-Myc in lipofibroblasts is necessary for the development, proliferation and maintenance of myofibroblasts after bleomycin-mediated lung injury. From a therapeutic point of view, the control of the differentiation status of the myofibroblasts is almost completely unexplored. The proposed studies should significantly advance our knowledge of pulmonary fibrosis: (i) by identifying the origin of the cells that give rise to myofibroblasts in pulmonary fibrosis; (ii) by validating the concept of manipulating lipofibroblast to myofibroblast transdifferentiation as well as the reverse process as an intriguin new therapeutic option for the treatment of fibroproliferative lung diseases; (iii) by identifying -Myc as the main driver of LIF to MYF transdifferentiation and their subsequent proliferation, and as such validating c-Myc as a potential therapeutic target to treat pulmonary fibrosis.

描述：HL-131：特发性肺fitf的发病机理不理并没有治愈。这会产生肌纤维细胞及其分化的机制。与周围或野生型相比，C-Myc本身（在不存在肺损伤的情况下）是高水平的C-YC，α-SMA和胶原蛋白。在肌纤维细胞中，通过促进裂解的肺肺疾病来促进iTol iTol iTol iTOL脂肪纤维细胞，这些假设将通过特定的目标解决三个特定的目标。小鼠2中的FIRLOSOS将检验C- Myc是非常差异的甲脱脂剂，其差异及其差异统计数据3我们将测试脂肪纤维中的C-Myc。博来霉素介导的肺部损伤后，肌纤维细胞的发育，肌纤维细胞的融合。在治疗纤维增生性肺部疾病（III）中，新的治疗选择是通过识别-MyC作为LIFSDIFERTICTION的驱动力及其随后的蛋白质蛋白。