miR-21 and lung fibrosis

miR-21与肺纤维化

• 批准号: 8115680
• 负责人: Gang Liu
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115680
• 关键词: Affect; Apoptosis; Attenuated; Bleomycin; Cardiovascular Diseases; Cell Proliferation; Cell Survival; Data; Development; Diabetes Mellitus; Disease; Etiology; Event; Fibroblast Growth Factor 2; Fibroblasts; Fibrosis; Gene Targeting; Goals; Hamman-Rich syndrome; Human; Human Activities; Interstitial Lung Diseases; Lung; MAP Kinase Gene; Malignant Neoplasms; Mediating; MicroRNAs; Molecular; Mus; Myofibroblast; PTEN gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Process; Property; Proteins; Pulmonary Fibrosis; Regulation; Role; Severities; Signal Transduction; effective therapy; fibrogenesis; improved; in vivo; indium-bleomycin; injury and repair; lung injury; novel therapeutic intervention; novel therapeutics; prevent; response

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is one of the most pernicious forms of lung fibrogenesis and currently has no clearly effective treatments. Whereas the etiology of IPF remains enigmatic, there is evidence of dysregulations of several major molecular pathways in lung fibroblasts of IPF patients, including apoptosis/survival pathways as well as TGF-¿, Akt, and MAPK signaling. In our preliminary studies, we found that the expression of miR-21 is upregulated in the lungs of mice with bleomycin-induced lung fibrosis and in the lungs of patients with IPF. Target predictions as well as previous studies demonstrate that miR-21 regulates the expression of PDCD4, Smad7, Spry1, and PTEN. These proteins are critical negative regulators of cell proliferation and survival as well as TGF-¿, PI3K, and MAPK signaling. This information, together with our preliminary data, suggests that miR-21 may play an important role as an integrator in initiation and progression of IPF. Therefore, miR-21 appears to be a potential target for developing novel therapeutics to treat IPF. Our preliminary data showing that sequestering miR-21 by anti-miR-21 probes diminishes the severity of bleomycin induced lung fibrosis lend a strong support to this hypothesis. In this proposal, we aim to 1) characterize miR-21 expression in human lung fibroblasts, in the lungs of mice with bleomycin induced pulmonary fibrosis and in the lungs of patients with IPF; 2) delineate the role of miR-21 in vivo during bleomycin induced lung fibrosis; 3) delineate the mechanisms by which miR-21 regulates lung fibrosis; 4) delineate the role of miR-21 in modulating the ex vivo pathological properties of lung fibroblasts from IPF patients. PUBLIC HEALTH RELEVANCE: MicroRNAs are important regulators of many essential cellular and developmental events. Deregulations of microRNA expression have been shown to be involved in a number of diseases, such as cancer, cardiovascular diseases, and diabetes. However, whether microRNAs regulate lung injury and repair, processes that occur in idiopathic pulmonary fibrosis (IPF) has not been elucidated. We found that the expression of miR-21 is upregulated in mouse lungs with bleomycin induced lung fibrosis and lungs of patients with IPF and miR-21 promotes the fibrogenic activity of TGF-¿ in human fibroblasts. The studies proposed in this application should not only improve understanding of the roles of miR-21 in the pathogenesis of lung fibrosis, but also are likely to suggest novel therapeutic interventions aimed at decreasing the severity of lung fibrosis.

描述（由适用提供）：特发性肺纤维化（IPF）是最有害的肺​​纤维发生形式之一，目前尚无明显有效的治疗方法。尽管IPF的病因仍然是神秘的，但有证据表明IPF患者肺成纤维细胞中几种主要分子途径的失调，包括凋亡/生存途径以及TGF- - ，AKT和MAPK信号传导。在我们的初步研究中，我们发现MiR-21的表达在具有博来霉素诱导的肺纤维化和IPF患者肺的小鼠的肺中进行了更新。目标预测以及以前的研究表明，miR-21调节PDCD4，SMAD7，SPRY1和PTEN的表达。这些蛋白质是细胞增殖和存活的关键负调节剂，以及TGF- - ，PI3K和MAPK信号传导。这些信息以及我们的初步数据表明，miR-21在IPF的启动和进展中可能起重要作用。因此，miR-21似乎是开发新型治疗IPF的潜在靶标。我们的初步数据表明，抗MIR-21隔离miR-21探测会降低博来霉素诱导的肺纤维化的严重程度为这一假设提供了强有力的支持。在此提案中，我们的目的是1）表征人类肺成纤维细胞中的miR-21表达，在具有博来霉素诱导的肺纤维化和IPF患者肺的小鼠的肺中； 2）描述miR-21在体内在博来霉素诱导的肺纤维化中的作用； 3）描述miR-21调节肺纤维化的机制； 4）描述miR-21在调节IPF患者肺纤维化的离体病理特性中的作用。 公共卫生相关性：microRNA是许多基本细胞和发育事件的重要调节因子。 MicroRNA表达的不含量已显示出与多种疾病有关，例如癌症，心血管疾病和糖尿病。但是，无论是调节肺损伤和修复的microRNA，是否尚未阐明特发性肺纤维化（IPF）中发生的过程。我们发现，在患有博霉素诱导的肺纤维化的小鼠肺中，miR-21的表达进行了更新，而IPF和miR-21患者的肺则促进了人类成纤维细胞中TGF- - 的纤维化活性。在本应用中提出的研究不仅应提高对miR-21在肺纤维化发病机理中的作用的理解，而且还可能提出旨在降低肺纤维化严重程度的新型治疗干预措施。