Research & Publications
Dr. Yu got his BS, MS and PhD in the Henan Normal University, Yunnan University, and The Chinese Academy of Sciences in the Peoples' Republic of China respectively. He joined Dr. Kaminski' research group in 2006 in University of Pittsburgh and completed his research fellow training on pulmonary. Dr. Yu has undertaken basic and translational investigations into the pathogenesis of idiopathic pulmonary fibrosis (IPF).
IPF is a progressive, scarring of the alveolar parenchyma that ultimately leads to respiratory failure and death. Pathologically, this disease is characterized by the epithelial cell injury and unremitting accumulation of fibroblasts. These are the cells responsible for the deposition of extracellular matrix in pulmonary fibrosis. To gain insight into the pathogenesis of IPF, Based on gene expression profiling of IPF lungs compared to normal controls, we focus on the genes that exhibited altered expression in IPF under the rationale that genes likely contribute to the development of pulmonary fibrosis. Specifically, I have focused on MMP19, miR-29 and DIO2. i.e. currently I’m focusing on exploring the role and regulation of MMP19, miR-29 and thyroid hormone in human pulmonary fibrosis.
We made the novel insights that microRNA mir-29 is decreased in expression in patients with IPF, therapeutic delivery of these miR-29 mimics during bleomycin-induced pulmonary fibrosis can increase level of miR-29 in vivo and restores endogenous miR-29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis. Our data support the feasibility of using miRNA mimics to therapeutically increase miRNAs and indicate miR-29 to be a potent therapeutic miRNA for treating pulmonary fibrosis. Upcoming works include testing the efficacy of miR-29 mimc in different animal models and various approaches.
Using laser capture microdissection (LCM) and gene expression microarray, we discovered that MMP-19 is significantly increased in hyperplastic epithelial cells adjacent to fibrotic regions in IPF lungs. MMP-19 was required for normal cellular wound healing in vitro, and the loss of MMP-19 worsened bleomycin-induced fibrosis in vivo, likely by inducing the expression of cyclooxygenase-2. These data indicate that MMP-19 is a critical regulator of alveolar epithelial cell response to injury. And also MMP19 is associated with the development and progression of lung cancer and may be a potential biomarker of disease severity and outcome. We found that overexpression of MMP19 promotes epithelial–mesenchymal transition, migration, and invasiveness in multiple NSCLC cell lines. Overexpression of MMP19 with a mutation at the catalytic site did not impair epithelial–mesenchymal transition or expression of prometastasis genes. We also found that miR-30 isoforms, a microRNA family predicted to target MMP19, is markedly down-regulated in human lung cancer and regulates MMP19 expression. Currently we are working on exploring the further molecular mechanism, mainly on ER stress signaling.
Thyroid hormone (TH) metabolism regulated by three iodothyronine deiodinases (DIO1-3) is critical for maintenance of cellular homeostasis during stress responses, but its role in lung fibrosis is unknown. The third, most recently but most importantly, we first investigated the role of thyroid hormone in pulmonary fibrosis and demonstrated that DIO2 was one of the most upregulated genes that differentiated patients with IPF from controls. We discovered that DIO2 expression and activity was increased in IPF lungs and correlated with disease progression. Genetic ablation of DIO2 enhanced bleomycin-induced lung fibrosis. Aerosolized TH delivery increased survival and resolved fibrosis in two models of murine pulmonary fibrosis. Oral Sobetirome (GC-1), a TH small molecule mimetic also blunted bleomycin-induced lung fibrosis. Given after bleomycin injury, TH induced mitochondrial biogenesis and autophagic flux, improved mitochondrial bioenergetics and attenuated mitochondria-regulated apoptosis in alveolar epithelial cells both in-vivo and in-vitro. TH did not blunt fibrosis in PPARGC1A or PINK1 knockout mice suggesting that TH anti-fibrotic effects are dependent on intact PPARGC1A and PINK1 pathways. We conclude that TH treatment exerts epithelial protective anti-fibrotic properties associated with restoration of alveolar epithelial cells mitochondrial function and homeostasis and thus may represent an effective therapy for Pulmonary Fibrosis. Upcoming works include exploring the role and regulation of thyroid hormone in human pulmonary fibrosis and other lung diseases.
Education & Training
- PhDChinese Academy of Medical Sciences (1995)
- MSYunnan University (1990)
- BSHenan Normal University (1987)
- FellowshipUniversity of Pittsburgh School of Medicine