Control of fibrosing lung disease by p53-miR-34a-targeted therapeutics

通过 p53-miR-34a 靶向疗法控制纤维化肺疾病

• 批准号: 9276124
• 负责人: Sreerama Shetty
• 金额: $ 39.18万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276124
• 关键词: Address; Affect; Alveolar; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Architecture; Biochemical; Bleomycin; Cell Differentiation process; Cells; Cicatrix; Cytoskeletal Modeling; Data; Deposition; Development; Diagnosis; Disease; Epithelial; Epithelial Cells; Etiology; Europe; Extracellular Matrix; Fibroblasts; Fibrosis; Functional disorder; Generations; Hamman-Rich syndrome; Histologic; Human; Imaging Techniques; Interstitial Lung Diseases; Intervention; Knockout Mice; Lung; Lung diseases; Mediating; MicroRNAs; Modeling; Molecular; Mus; Myofibroblast; PDGFRB gene; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Platelet-Derived Growth Factor; Population; Process; Production; Proliferating; Property; Protein p53; Proteins; Pulmonary Fibrosis; Regulation; Reporting; Resistance; Respiratory physiology; Role; Signal Transduction; Structure of parenchyma of lung; TP53 gene; Tertiary Protein Structure; Testing; Time; Tissues; Tumor Suppressor Proteins; Ubiquitination; Work; attenuation; base; caveolin 1; feeding; improved; improved outcome; interstitial; lung injury; migration; molecular imaging; novel; outcome forecast; prevent; repaired; response; restoration; scaffold; targeted treatment

Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease and is fatal. It affects 500,000 people in the USA and Europe per year with a median survival of <2-3 years after diagnosis. Its pathogenesis is poorly understood and there is no cure. A hallmark of IPF is the formation of fibroblastic foci, consisting of large numbers of fibrotic lung fibroblasts (fLFs) and interstitial fibrosis with architectural distortion. The population of fLFs in the lungs of patients with IPF includes myofibroblasts and activated highly proliferative, migratory fibroblasts that deposit excessive matrix proteins. Our preliminary data demonstrate that basal expression of p53 and microRNA-34a (miR-34a), are markedly reduced, while expression of platelet derived growth factor- (PDGFR- is significantly increased in fLFs from IPF lungs compared with control fibroblasts extracted from histologically “normal” lungs (nLFs). This also occurs in mice with bleomycin (BLM)-induced pulmonary fibrosis (PF). In addition, p53 and miR-34a act through an autoregulatory feed-forward loop, which in turn suppresses PDGFR-. Our working hypothesis is that p53 and miR-34a are reduced in fLFs, which induce pro-fibrogenic responses in fLFs that are critical to the pathogenesis of PF. We infer that restoration of p53 and miR-34a in fLFs will mitigate PF. Our objective is to elucidate the mechanism by which reduced p53 and miR-34a expression in fLFs promote PF. We will also determine if targeting of this pathway suppresses pro-fibrogenic properties of fLFs and thereby reverses established PF. The peptide CSP7 (FTTFTVT) will be used to target this pathway. We have previously shown that the p53-targeting with CSP7 blocks alveolar epithelial apoptosis and prevents development of BLM-induced PF. However, the effects of CSP7 on fLFs are unknown, as is how targeting of the p53/miR-34a pathway in these cells resolves established PF. These represent potentially critical gaps in our understanding of the pathogenesis of PF and will be addressed in this project. Our Aims are: 1) To elucidate the role of p53 in pro-fibrogenic responses in fLFs. We will define mechanism by which p53 regulates pro-fibrogenic responses of fLFs and test the ability CSP7 to block these responses in fLFs from patients with IPF and from mice with BLM- or TGF--induced PF. 2) To determine how miR-34a regulates p53-mediated pro-fibrogenic responses in fLFs. We will define the role of altered miR-34a expression in the control of these responses in fLFs and test whether the same interventions reverse the miR- 34a-mediated responses. 3) To elucidate the signaling mechanisms involved in p53- and miR-34a-mediated regulation of pro-fibrogenic responses in LFs. State of the art modeling, biochemical, molecular and imaging- based approaches will be used to accomplish the aims. This project will have a major impact on the field by determining, for the first time, how p53 and miR-34a regulate pro-fibrotic responses including changes in PDGFR- in fLFs and PF. The work may also define novel, p53/miR-34a-targeted approaches to reverse these effects and improve outcomes for patients with IPF.

特发性肺纤维化（IPF）是最常见的间质性肺疾病，是致命的。它影响了500,000 诊断后，美国和欧洲的人每年的生存中位数<2 - 3年。它的发病机理 理解不足，无法治愈。 IPF的标志是成纤维细胞灶的形成，由 大量的纤维化肺成纤维细胞（FLF）和间质性纤维化具有建筑失真。 IPF患者肺中FLF的种群包括肌纤维细胞，并激活高度增殖， 迁移的成纤维细胞沉积多余的基质蛋白。我们的初步数据证明了基本 p53和microRNA-34A（miR-34a）的表达明显降低，而血小板的表达得出 生长因子-（与对照成纤维细胞相比，IPF肺FLF的PDGFR-显着增加 从组织学上的“正常”肺（NLF）中提取。这也发生在具有博来霉素（BLM）诱导的小鼠中 肺纤维化（PF）。此外，p53和miR-34a通过自动调节馈送循环起作用，该回路 反过来抑制PDGFR-。我们的工作假设是，p53和miR-34a在FLF中减少了，这是 在FLF中诱导促纤维化反应，这对PF的发病机理至关重要。我们推断出的恢复 FLF中的p53和miR-34a将减轻PF。我们的目标是阐明降低p53的机制 FLF中的miR-34a表达促进了PF。我们还将确定该途径的靶向是否抑制 FLF的促纤维化特性，从而逆转已建立的PF。辣椒CSP7（FTTFTVT）将是 用于针对此途径。我们以前已经表明，用CSP7阻止肺泡的p53靶向 上皮凋亡并防止BLM诱导的PF的发展。但是，CSP7对FLF的影响是 未知，这些细胞中p53/miR-34a途径的靶向方式也是如此。这些 在我们对PF发病机理的理解中代表潜在的关键差距，并将在此解决 项目。我们的目的是：1）阐明p53在FLF中促纤维化反应中的作用。我们将定义 p53调节FLF的促纤维化反应并测试CSP7阻止这些能力的机制 IPF患者和患有BLM或TGF-诱导的PF的小鼠的FLF的反应。 2）确定如何 miR-34a调节FLF中P53介导的促纤维化反应。我们将定义改变miR-34a的作用 在FLF中控制这些反应的表达，并测试相同的干预措施是否逆转miR- 34A介导的响应。 3）阐明涉及p53-和miR-34a介导的信号传导机制 LFS中促纤维化反应的调节。最先进的建模，生化，分子和成像 - 基于基于的方法将用于实现目标。该项目将对该领域产生重大影响 首次确定p53和miR-34a如何调节促纤维化反应，包括变化 pdgfr-在FLF和PF中。这项工作还可以定义小说，p53/mir-34a靶向的方法来扭转这些方法 IPF患者的影响并改善结果。