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Mechanisms of cardiac and pulmonary fibrosis in relation to TGF-beta signaling and miR-145 function

心脏和肺纤维化与 TGF-β 信号传导和 miR-145 功能相关的机制

基本信息

批准号：
9536947
负责人：
Simon James Conway
金额：
$ 42.13万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9536947
关键词：
Adrenergic Agents Attenuated Bleomycin Cardiac Cell Lineage Cell Separation Cells Cicatrix Collaborations Complex Data Development Disease Disease Management Disease Progression Disease model Excision Exhibits Familiarity Fibroblasts Fibrosis Genetic Genetic Transcription Goals Heart Heart Diseases Homeostasis Hyperoxia Inflammation Knock-in Knock-out Knockout Mice Lead Lung Lung diseases Mediator of activation protein MicroRNAs Mouse Strains Mus Myofibroblast Organ Organ failure Outcome Pathologic Pathology Phenotype Play Population Positioning Attribute Proteins Pulmonary Fibrosis Reporting Research Personnel Role Signal Pathway Signal Transduction Stress Testing Therapeutic Tissues Transforming Growth Factor beta Transgenes Transgenic Mice Transgenic Organisms Up-Regulation Wound Healing cell type coronary fibrosis epithelial to mesenchymal transition experience fibrogenesis gain of function interstitial loss of function mouse model novel novel therapeutic intervention overexpression periostin response response to injury tool transcriptome sequencing treatment strategy

项目摘要

SUMMARY We identified a novel function for microRNA miR145 in the suppression of cardiac fibrosis using miR145- deficient mice. It has also been reported that miR145 enhances pulmonary fibrosis, and that miR145 can drive myofibroblast (myoF) differentiation within both cardiac and lung fibroblasts (Fbs). Together these data suggest that mechanistic differences between cardiac and pulmonary fibrosis may reflect differences in cell type contribution and dissimilar actions of miR145 upon Fbs. Preliminary data reveal that miR145 targets components of the profibrotic TGFß signaling pathway, which is a central mediator of cardiac and pulmonary fibrosis. Furthermore, we have shown that a downstream TGFß effector, Periostin (Postn) is upregulated in myoFs in cardiac and pulmonary fibrosis. Postn has been proven to play an important role in fibrogenesis in many organs in which it is activated during the Fb-myoF transition. Additional preliminary data reveal that within the heart, systemic deletion of Postn correlates with decreased fibrosis but unlike the heart, the absence of Postn results in elevated lung fibrosis. The overall objective of this application is to define the distinct cell- specific mechanisms that contribute to cardiac and pulmonary fibrosis. Our data suggest that suppression of TGFß signaling by miR145 and/or removal of TGFß-responsive downstream effectors like Postn may be employed to modulate fibrosis. Our central hypothesis is that cardiac and pulmonary fibrosis exhibit different mechanisms due to variances in the contributing cell populations and organ-specific transcriptional milieu. While TGFß signaling drives both pathologies and upregulation of Postn, the cell microenvironment dictates disease progression. Cardiac fibrosis manifests primarily through stress-induced activation of CFs, while pulmonary fibrosis involves epithelial-to-mesenchymal transitions, inflammation and resident Fb activation. Using cell-specific loss-of-function and gain-of-function strategies to modulate miR145, we will determine the cell types that contribute to the contrasting functions of miR145 in cardiac and pulmonary fibrosis. This co- investigator team is well positioned to test this hypothesis, with a prior track record of collaboration and expertise. The Lilly lab has generated a novel miR145 transgenic mouse strain, and is experienced with microRNA analyses. The Conway lab brings extensive experience in both cardiac and pulmonary disease models, and expertise in Postn and Fb activation. The goal of the aims is to determine the cell type-specific requirement of miR145 to regulate fibrosis with the intent of elucidating novel distinctive mechanisms associated with pulmonary and cardiac fibrosis. Aim 1) Delineate the mechanisms that differentially govern cardiac and pulmonary fibrosis. Aim 2) Determine if lineage-restricted overexpression of a miR145 transgene alters pulmonary and/or cardiac fibrosis. These expected outcomes will elucidate mechanisms contributing to cardiac and pulmonary fibrosis via determination of how miR145 regulates cell-specific fibrosis.

总结