Research Project
10256727
Summary/Abstract: Fibrotic diseases are associated with high morbidity and mortality. Pulmonary fibrosis (PF) is a progressive disease with no effective treatment except lung transplant. PH is also a risk factor for other health complications including lung cancer. A major characteristic of PF is increased deposition of extracellular matrix (ECM) that leads to lung tissue stiffening and loss of function. PF is a heterogeneous disease characterized by aberrant signaling pathways of oxidative stress (OS), TGF?, and NF-?B. We have previously reported increased ROS and activation of MAPK, NF-?B, and TGF? in alveolar epithelial cells following treatment with known lung fibrotic toxicants silica and multi-walled carbon nanoparticles (MWCNT). Our previous studies also showed increased expression of Col3A1 and TGF? in alveolar epithelial cells in response to MWCNT. While PF is multifactorial, studies have linked reactive oxygen species (ROS) and aberrant microRNAs (miRs) in lung fibrosis development. How exactly ROS regulate miRs that drive lung fibrosis development remains largely unknown and is the focus of the present application. In our study of human alveolar epithelial (A549) cells exposed to MWCNT, we found that: (1) miR-1 is downregulated; (2) TSP-1 is up-regulated; and (3) exogenous mimic miR-1 suppresses TSP-1, a major activator of TGF?. These findings suggest that miR-1 and TSP-1 are regulated by MWCNT and targeting miR-1 and TSP-1 might inhibit TGF?-mediated fibrotic response. The central hypothesis of the current project is that ROS suppress miR-1 which promotes increased TSP-1 and active TGF? fibrotic signaling. Specific aims are: (1) determine the mechansims by which miR-1 is regulated; (2) determine the mechanistic link between miR-1 and fibrotic signaling via TSP-1/TGF? (or other pathways emerging from mRNASeq data); and (3) determine the function of miR-1 in lung fibrosis in vivo by analyzing whether a model of bleomycin- and MWCNT-lung fibrosis in mice and exogenous miR-1 treated mice are less prone to lung fibrosis than control miR-1 untreated mice. The proposed study will elucidate cellular and molecular mechanism involved in lung fibrosis by targeting TSP-1 via miR-1. This hypothesis, if proven, will establish a potential microRNA therapy in pulmonary fibrosis.
