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Role of Smad3 in obiliterative bronchiolitis

Smad3 在闭塞性细支气管炎中的作用

基本信息

批准号：
8113175
负责人：
ALLAN RAMIREZ
金额：
$ 12.83万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113175
关键词：
Address Affect Agonist Allografting Animal Model Biopsy Specimen Bronchioles Bronchiolitis Cells Chronic Clinical Collagen Type I Complex Connective Tissue Contractile Proteins Cysteine Cystine DNA Binding Deposition Development Disease Disulfides Effector Cell Engineering Event Experimental Models Extracellular Matrix Fibroblasts Fibronectins Functional disorder Future Genes Genetic Transcription In Vitro Inflammatory Injury Integrins Investigation Lesion Lung Lung Transplantation Lymphocyte Mediating Mononuclear Myofibroblast Nuclear Oxidants Oxidation-Reduction Oxidative Stress Pathogenesis Pathway interactions Peroxisome Proliferator-Activated Receptors Phenotype Preparation Prevention strategy Process Proteins Recovery Regulation Relative (related person)Research Research Personnel Role Salvage Therapy Signal Pathway Signal Transduction Smooth Muscle Actin Staining Method Stress Sulfhydryl Compounds T-Cell Activation Testing Transducers Transforming Growth Factors Transplant Recipients Transplantation Up-Regulation Work abstracting allograft rejection arm career design directed attention effective therapy extracellular in vivo isoimmunity macrophage meetings novel oxidant stress oxidation prevent programs receptor success tool transcription factor transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): Obliterative bronchiolitis (OB), considered to be a manifestation of chronic allograft dysfunction in lung transplant recipients, is an irreversible fibroproliferative process that represents the major barrier to long term survival. Hence, research directed at identifying the factors involved in the development of OB in lung transplant recipients is paramount to finding effective treatment for this otherwise untreatable disease. We have found that Transforming Growth Factor-p (TGFp) via its signal transducer, SmadS, is necessary for the development of OB as well as the myofibroblast transdifferentiation that accompanies OB. Hence, we have focused on the mechanisms regulating TGFp/Smad signaling in OB and have made a number of key observations. First, oxidation of the extracellular cysteine-cystine (Cys/CySS) redox couple induces upregulation and activation of TGFp and SrnadS. Second, SmadS expression and DNA binding in lung fibroblasts, and consequently, myofibroblast transformation, is augmented by aberrant transitional matrix, components, e.g., fibronectin and type I collagen, which are invariably found in the setting of OB. And third, activation of the nuclear transcription factor, peroxisome proliferator-activated receptor-y (PPARy), inhibits TGFpl -induced myofibroblast transdifferentiation by disrupting SmadS-dependent gene transcription. These findings led us to the hypothesis that activation of TGFp1/Smad3 signaling in airway fibroblasts is a critical driver of myofibroblast transdifferentiation in OB that is intensified by the presence of chronic extracellular oxidant stress, aberrant transitional matrices, and defective PPARy signaling. This hypothesis will be tested in fibroblast cultures and in experimental models of OB in three specific aims designed to: 1) examine the mechanisms by which chronic extracellular oxidative stress activates TGFp1/Smad3-dependent signaling events in vitro and in vivo through the Cys/CySS redox couple 2) examine how transitional matrices promote activation of TGFpl /SmadS signaling and myofibroblast transdifferentiation through integrin-dependent signals 3) determine the mechanisms by which PPARy affects the SmadS signaling pathway and the induction of myofibroblast transdifferentiation and matrix expression in experimental OB. These complex issues will be addressed with the assistance of expert advisors and collaborators with the broader objective of unveiling novel targets for therapy. (End of Abstract)

描述（由申请人提供）：