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 TGF signaling pathway, which is a central mediator of cardiac and pulmonary fibrosis. Furthermore, we have shown that a downstream TGF 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 TGF signaling by miR145 and/or removal of TGF-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 TGF 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.

Public Health Relevance

Tissue fibrosis, or uncontrolled wound healing, is a pathological condition that leads to loss of tissue homeostasis and eventual organ failure. Enhanced TGF signaling is associated with both pulmonary and cardiac fibrosis, yet it is not clear if the mechanisms are the same. This proposal will investigate the mechanistic relationship of microRNA miR145 and Periostin, both of which have been implicated in pulmonary and cardiac fibrosis and may serve as entry points to disease management. These studies are poised to elucidate the common and unique mechanisms associated with tissue fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL135657-01A1
Application #
9382422
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2017-08-01
Project End
2021-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Liu, Hua; Zhang, Wenbo; Lilly, Brenda (2018) Evaluation of Notch3 Deficiency in Diabetes-Induced Pericyte Loss in the Retina. J Vasc Res 55:308-318
Lilly, Brenda; Dammeyer, Kristen; Marosis, Sam et al. (2018) Endothelial cell-induced cytoglobin expression in vascular smooth muscle cells contributes to modulation of nitric oxide. Vascul Pharmacol 110:7-15