WT1 REGULATION OF PULMONARY FIBROSIS

WT1 肺纤维化的调节

• 批准号: 9925244
• 负责人: Satish K Madala
• 金额: $ 38.99万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-22 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925244
• 关键词: Adult; American; Area; Attenuated; Biochemical; Bioinformatics; Biological Assay; Bleomycin; Cell Culture Techniques; Cells; Cicatrix; Clinical; Complex; Coupled; Data; Deposition; Diagnosis; Disease; Extracellular Matrix; Fibroblasts; Fibronectins; Fibrosis; Future; Gases; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Goals; Health; Hydroxyproline; Impairment; In Vitro; Intervention; Knowledge; Lead; Lesion; Luciferases; Lung; Lung diseases; Medical; Mesenchymal; Mitotic; Molecular; Mus; Pathogenesis; Pathologic Processes; Pathology; Patients; Peripheral; Phenotype; Phosphotransferases; Play; Prevention; Process; Production; Pulmonary Fibrosis; Pulmonary Pathology; Reporter; Reporting; Research; Respiratory physiology; Role; Structure of parenchyma of lung; Systems Biology; Techniques; Testing; Time; Tissues; Transducers; Transforming Growth Factor alpha; Transgenic Mice; Up-Regulation; Validation; WT1 gene; Zinc Fingers; aurora kinase A; base; design; effective therapy; experimental study; idiopathic pulmonary fibrosis; improved; in vivo; innovation; insight; mortality; mouse model; multidisciplinary; novel; novel therapeutic intervention; novel therapeutics; overexpression; programs; promoter; therapeutic target; transcription factor; transcriptome sequencing; translational study; treatment strategy

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that is incurable due to the formation of scar tissue and resultant impaired lung function. Approximately 130,000 Americans suffer from IPF, with an estimated 50,000 new cases diagnosed each year. Mortality rates from pulmonary fibrosis have increased significantly in recent years, thereby increasing the demand for pulmonary fibrosis research. Although it is well accepted that fibrosis is a central component of pathogenesis in IPF, the transcriptional program(s) that orchestrate fibrotic processes are poorly defined and represent a major knowledge gap in the field. WT1 is a zinc-finger transcriptional regulator, the function of which has been poorly studied in adult fibrotic lung diseases. We have recently reported direct clinical evidence of WT1 upregulation in lung mesenchymal cells of fibrotic lesions in IPF patients. Our new findings have determined that WT1 functions as a positive regulator of fibroproliferation and ECM production. In support of this, we identified a positive association between the number of WT1-positive cells and total lung hydroxyproline levels in mouse models of TGFα- and bleomycin- induced pulmonary fibrosis. Further, inhibition of WT1 expression in vivo was sufficient to attenuate fibrosis in the lung. Taken together, these findings lead us to postulate that WT1 functions as a positive regulator of fibroproliferation and ECM production in the pathogenesis of pulmonary fibrosis. For this study, we propose three specific aims: 1) determine whether reduced WT1 expression is sufficient to attenuate fibrproliferation and ECM production; 2) determine whether mesenchymal cell-specific expression of WT1 is critical in the pathogenesis of pulmonary fibrosis; and 3) determine the mechanism by which WT1 promotes fibroproliferation and ECM production. We will use complementary primary mesenchymal cell culture and mouse transgenic approaches, coupled with detailed biochemical analysis of these WT1-driven processes in mouse lung tissues. Completion of the proposed experiments is likely to impart a significant understanding of WT1-driven pulmonary fibrosis and its transducers, which may be targeted in the future using novel therapeutics to attenuate pulmonary fibrosis. The multidisciplinary team will facilitate a timely approach with expertise in all aspects of lung pathology and support future translational studies in IPF. Our approach is innovative due to the generation of novel transgenic mice to test WT1 functions and its targets involved in the pathology of pulmonary fibrosis. The proposed research is significant in that completion of this study will increase an understanding of the mechanisms causing IPF, which in turn will lead to advanced medical therapies for the treatment and possible cure or prevention of this debilitating lung disease.

项目摘要 特发性肺纤维化（IPF）是一种进行性肺部疾病，由于瘢痕形成而无法治愈 组织并导致肺功能受损。大约13万美国人患有IPF， 估计每年有5万例新确诊病例。肺纤维化的死亡率增加 近年来，肺纤维化的研究取得了显著进展，从而增加了对肺纤维化研究的需求。虽然是井 接受纤维化是IPF发病机制的中心组成部分， 协调纤维化过程的定义很差，代表了该领域的主要知识空白。WT 1是一个 锌指转录调节因子，其在成人纤维化肺中的功能研究很少 疾病我们最近报道了直接的临床证据，即在肺间充质细胞中WT 1上调， IPF患者的纤维化病变。我们的新发现已经确定WT 1作为一个积极的调节因子， 纤维增生和ECM产生。为了支持这一点，我们确定了一个积极的关联之间的 TGFα-和博莱霉素-小鼠模型中WT 1阳性细胞数和总肺羟脯氨酸水平 诱发肺纤维化。此外，在体内抑制WT 1表达足以减弱纤维化。 肺综上所述，这些发现使我们假设WT 1作为一种正调节因子发挥作用， 肺纤维化发病机制中的纤维增殖和ECM产生。在这项研究中，我们 提出三个具体目标：1）确定减少的WT 1表达是否足以减弱 间充质细胞增殖和ECM产生; 2）确定间充质细胞特异性表达WT 1是否是间充质细胞增殖和ECM产生的关键因素。 在肺纤维化的发病机制中至关重要; 3）确定WT 1促进肺纤维化的机制。 纤维增生和ECM产生。我们将使用补充的原代间充质细胞培养， 小鼠转基因方法，加上这些WT 1驱动的过程的详细生化分析， 小鼠肺组织。完成拟议的实验可能会对以下方面有重要的了解： WT 1驱动的肺纤维化及其换能器，这可能是在未来的目标，使用新的 减轻肺纤维化的治疗剂。多学科小组将促进及时采取办法， 在肺病理学的所有方面的专业知识，并支持未来的转化研究在IPF。我们的做法是 创新，由于新的转基因小鼠的产生，以测试WT 1的功能和它的目标，参与 肺纤维化的病理学这项研究的意义在于，完成这项研究将 增加对IPF发病机制的了解，这反过来又会导致先进的医学 用于治疗和可能治愈或预防这种使人衰弱的肺病的疗法。