miR-21 and lung fibrosis

miR-21与肺纤维化

• 批准号: 8434914
• 负责人: Gang Liu
• 金额: $ 34.87万
• 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/8434914
• 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.

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，目前尚无明确有效的治疗方法。尽管IPF的病因仍然是个谜，但有证据表明IPF患者肺成纤维细胞中的几种主要分子途径失调，包括细胞凋亡/存活途径以及TGF-β、Akt和MAPK信号传导。在我们的初步研究中，我们发现miR-21的表达在博莱霉素诱导的肺纤维化小鼠的肺和IPF患者的肺中上调。靶点预测以及先前的研究表明，miR-21调节PDCD 4、Smad 7、Spry 1和PTEN的表达。这些蛋白质是细胞增殖和存活以及TGF-β、PI 3 K和MAPK信号传导的关键负调节剂。这一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的整合作用。因此，miR-21似乎是开发治疗IPF的新疗法的潜在靶点。我们的初步数据显示，通过抗miR-21探针隔离miR-21降低了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。在本研究中，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肺和IPF患者肺中的表达; 2）描述miR-21在博来霉素诱导的肺纤维化过程中的体内作用; 3）描述miR-21调节肺纤维化的机制; 4）描述miR-21在调节来自IPF患者的肺成纤维细胞的离体病理学性质中的作用。