miR-21 and lung fibrosis

miR-21与肺纤维化

• 批准号: 8248722
• 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/8248722
• 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; lung injury; lung repair; novel therapeutic intervention; novel therapeutics; prevent; public health relevance; 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（由申请人提供）：特发性肺纤维化（IPF）是肺纤维化最有害的形式之一，目前没有明确有效的治疗方法，除了 IPF 的病因仍然是个谜，有证据表明几个主要分子途径的失调。 IPF 患者的肺成纤维细胞，包括凋亡/生存途径以及 TGF-¿在我们的初步研究中，我们发现博来霉素诱导的肺纤维化小鼠的肺部以及 IPF 患者的肺部中 miR-21 的表达上调。证明 miR-21 调节 PDCD4、Smad7、Spry1 和 PTEN 的表达，这些蛋白是细胞增殖和存活以及 TGF-¿这些信息与我们的初步数据一起表明 miR-21 可能在 IPF 的发生和进展中发挥重要作用，因此，miR-21 似乎是开发新型药物的潜在靶点。我们的初步数据表明，通过抗 miR-21 探针隔离 miR-21 可减轻博来霉素诱导的肺纤维化的严重程度，这为这一假设提供了强有力的支持。在本提案中，我们的目标是 1) 表征 miR-21 在人肺成纤维细胞、博来霉素诱导的肺纤维化小鼠的肺部以及 IPF 患者的肺部中的表达；2) 描述 miR-21 在博来霉素诱导的体内作用过程中的作用；诱导肺纤维化；3) 描述 miR-21 调节肺纤维化的机制；4) 描述 miR-21 在调节 IPF 患者肺成纤维细胞的离体病理特性。 公共健康相关性：MicroRNA 是许多重要细胞和发育事件的重要调节因子，microRNA 表达失调已被证明与许多疾病有关，例如癌症、心血管疾病和糖尿病。特发性肺纤维化 (IPF) 中发生的修复过程尚未阐明。我们发现博来霉素诱导的小鼠肺中 miR-21 的表达上调。 IPF 患者的纤维化和肺部以及 miR-21 促进 TGF-¿本申请提出的研究不仅应该提高对 miR-21 在肺纤维化发病机制中的作用的理解，而且还可能提出旨在降低肺纤维化严重程度的新治疗干预措施。