The purpose of this proposal is to elucidate the mechanisms by which production of endogenous matrix components in the context of non-infectious lung injury drives unremitting lung inflammation and fibrosis by interacting with cognate receptors leading to the development of an invasive pro-fibrotic fibroblast phenotype. The primary insult of a noninfectious challenge such as that which occurs in idiopathic pulmonary fibrosis or asthma, leads to the generation of endogenous matrix breakdown products that are recognized by a variety of cell surface receptors including TLRs. Critical host defense systems such as surfactant proteins commence to thwart the pro-inflammatory signals produced by the interaction of matrix fragments with cognate receptors. Three inter-related projects are proposed in this application to investigate these mechanisms, two of which employ studies in human subjects with asthma or two which employ studies of subjects with idiopathic pulmonary fibrosis (IPF). Therefore, we propose a Human Sample Core to facilitate the safe and efficient collection of research data and specimens from human subjects and assure adequate phenotyping of subjects. There are several advantages to such a facility. First, consolidating subject recruitment prevents duplication of personnel effort in each research project. Second, standardized subject assessment assures uniformity of experimental data across all projects in this program. Third, assembling an experienced clinical research team helps to maximize subject safety through the course of each research protocol. Finally, the consolidated laboratory facility allows for a uniform subject database and standardized collection, processing and storage of biologic specimens for each project in this program.
In aim 1, we will recruit and screen approximately 100 subjects (20/year) with IPF and 150 subjects with asthma (50 mild, 50 severe) and 50 normal subjects to participate in the studies outlined in Projects 1-3.
In aim 2, subjects with severe IPF (20/year) receiving lung transplant will undergo bronchoscopy with bronchoalveolar lavage (BAL) in the operating suite for experiments outlined in Projects 1 and 2;150 subjects (30/year) asthmatic and normal subjects will undergo bronchoscopy with BAL, endobronchial biopsy and brushing to obtain ainway macrophages and epithelial cells, and airway fibroblasts for ex vivo experiments outlined in Projects 2 and 3.
In aim 3, lung specimens from 100 subjects with idiopathic pulmonary fibrosis undergoing lung transplant will be obtained for fibroblast invasion studies outlined in Project 1 and specimens obtained from bronchoscopy will be processed for experiments in Projects 2 and 3.
The presence of a Human Sample Core is critical to the success of this proposal, as it will be utilized by all the projects. It allows for uniform and efficient recruitment of subjects, appropriate phenotyping, safe use of bronchoscopy by experienced personnel and an organized, consolidated approach to sample processing, sample use by each project, storage and cataloging of samples and data management.
|Yu, Yen-Rei A; Hotten, Danielle F; Malakhau, Yuryi et al. (2016) Flow Cytometric Analysis of Myeloid Cells in Human Blood, Bronchoalveolar Lavage, and Lung Tissues. Am J Respir Cell Mol Biol 54:13-24|
|Liang, Jiurong; Jiang, Dianhua; Noble, Paul W (2016) Hyaluronan as a therapeutic target in human diseases. Adv Drug Deliv Rev 97:186-203|
|Li, Yuejuan; Liang, Jiurong; Yang, Ting et al. (2016) Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis. Matrix Biol 55:35-48|
|Xu, Yan; Mizuno, Takako; Sridharan, Anusha et al. (2016) Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. JCI Insight 1:e90558|
|Xie, Ting; Liang, Jiurong; Liu, Ningshan et al. (2016) Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis. J Clin Invest 126:3063-79|
|Huan, Caijuan; Yang, Ting; Liang, Jiurong et al. (2015) Methylation-mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo. Sci Rep 5:14910|
|Dong, Yingying; Geng, Yan; Li, Lian et al. (2015) Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice. J Exp Med 212:235-52|
|Thannickal, Victor J; Henke, Craig A; Horowitz, Jeffrey C et al. (2014) Matrix biology of idiopathic pulmonary fibrosis: a workshop report of the national heart, lung, and blood institute. Am J Pathol 184:1643-51|
|Blackwell, Timothy S; Tager, Andrew M; Borok, Zea et al. (2014) Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med 189:214-22|
|Liu, Xing-Jun; Zhang, Yanli; Liu, Tong et al. (2014) Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter. Cell Res 24:1374-7|
Showing the most recent 10 out of 19 publications