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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

基本信息

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
项目类别：
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

项目摘要

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）是最常见的肺间质性疾病，具有致命性。它影响了50万人