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: 9157281
• 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/9157281
• 关键词: Address; Affect; Alveolar; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Architecture; Biochemical; Bleomycin; 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; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Platelet-Derived Growth Factor; Population; Process; Production; Proliferating; Property; Protein p53; Proteins; Pulmonary Fibrosis; Regulation; Reporting; Resistance; Respiratory physiology; Role; Signal Transduction; Staging; Structure of parenchyma of lung; TP53 gene; Tertiary Protein Structure; Testing; Time; Tissues; Tumor Suppressor Proteins; Ubiquitination; Work; attenuation; base; biochemical model; 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病，具有致死性。影响了50万人 在美国和欧洲，每年有100万人在诊断后中位生存期<2-3年。其发病机制 人们对此知之甚少，也无法治愈。IPF的一个标志是成纤维细胞灶的形成，包括 大量纤维化肺成纤维细胞（fLF）和间质纤维化，伴有结构变形。的 IPF患者肺中的fLF群体包括肌成纤维细胞和活化的高度增殖性， 迁移性成纤维细胞，存款过多的基质蛋白。我们的初步数据表明， p53和microRNA-34 a（miR-34 a）的表达显著降低，而血小板衍生的 与对照成纤维细胞相比，来自IPF肺的fLF中生长因子-β（PDGFR-β）显著增加 从组织学上“正常”的肺（nLF）中提取。这也发生在博莱霉素（BLM）诱导的小鼠中。 肺纤维化（PF）。此外，p53和miR-34 a通过自身调节前馈环起作用， 进而抑制PDGFR-β。我们的工作假设是p53和miR-34 a在fLF中减少， 在fLF中诱导促纤维化反应，这对PF的发病机制至关重要。 fLF中的p53和miR-34 a将减轻PF。我们的目的是阐明减少p53的机制， 和miR-34 a在fLF中的表达促进PF。我们还将确定靶向该途径是否抑制 肽CSP 7（FTTFTVT）将被用于治疗fLF的促纤维化性质，从而逆转已建立的PF。 用来瞄准这条通道我们之前已经表明，用CSP 7靶向p53可以阻断肺泡 然而，CSP 7对fLF的作用是通过抑制上皮细胞凋亡和阻止BLM诱导的PF的发展来实现的。 目前尚不清楚，靶向这些细胞中的p53/miR-34 a通路如何解决已建立的PF。 代表了我们对PF发病机制的理解中潜在的关键差距，并将在本 项目我们的目的是：1）阐明p53在fLF促纤维化反应中的作用。我们将定义 p53调节fLF的促纤维化反应的机制，并测试CSP 7阻断这些反应的能力。 来自IPF患者和来自BLM或TGF-β诱导的PF小鼠的fLF的反应。2）为了确定 miR-34 a调节fLF中p53介导的促纤维化反应。我们将定义改变的miR-34 a在 在fLF中控制这些反应的表达，并测试是否相同的干预措施逆转了miR- 34 A的反应。3)为了阐明p53和miR-34 a介导的细胞凋亡的信号转导机制， 调节LF中的促纤维化反应。最先进的建模，生化，分子和成像技术- 将使用基于的方法来实现这些目标。该项目将对该领域产生重大影响， 首次确定p53和miR-34 a如何调节促纤维化反应，包括 这项工作也可能定义新的，p53/miR-34 a靶向的方法来逆转这些疾病。 并改善IPF患者的结局。