Idiopathic pulmonary fibrosis (IPF) and chronic lung allograft dysfunction (CLAD) are disorders characterized by the inexorable loss of lung function and death within 3-5 years of diagnosis. IPF and CLAD share features of relentless extracellular matrix (ECM) deposition and the lack of response to immunosuppressive therapy. Compelling preliminary evidence is presented in the 3 projects within this proposal that the progressive scarring inherent to both IPF and CLAD is the consequence of dysregulated crosstalk between the lung epithelium and the lung resident mesenchymal stromal cells. Although there are clear distinctions between mechanisms of IPF and CLAD, this common theme should be investigated for potential therapeutic benefit in each condition. Each of the 3 inter-related projects proposed in this application is strengthened by studies in human subjects including the collection of patient specimens. We propose a Human Core to facilitate the safe and efficient collection of research data and specimens from these human subjects. We will leverage access to the large UCLA lung transplant program to supply high-quality human samples for the 3 program projects in this application. Specifically, we will recruit and enroll 300 subjects listed for lung transplant, for any indication, to participate in a post-transplant registry and bronchoscopy sample study proposed in Project 3. Among these 300 subjects, those with a diagnosis of IPF will be recruited to also provide their explanted IPF lung tissues for Projects 1 and 2. All subjects will be entered into a registry and the samples will be linked to this robust longitudinal database for clinical phenotyping. The Human Core comprises an experienced team of investigators, clinical research staff and laboratory personnel who will support human subject research and biological sample collection and processing for each of the 3 projects. This team has successful collaboration across multiple projects during the past 5 years. Therefore, the combination of a high volume lung transplant program, investigators' expertise, and an established infrastructure for human subject research and sample collection, collectively amount to a one-of-a-kind resource to study IPF and CLAD.

Public Health Relevance

Future gains in understanding human lung fibrogenesis will be enhanced by studying high-quality patient- derived samples paired with carefully annotated clinical phenotypes and outcomes data. This Human Core will leverage access to a large lung transplant program, as well as our expertise with human subject research and biospecimen collection to support the research projects in this application. We believe this Human Core is crucial, feasible, and will help advance our understanding of mechanisms of both IPF and CLAD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108793-07
Application #
9743217
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Craig, Matt
Project Start
Project End
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Liang, Jiurong; Liu, Ningshan; Liu, Xue et al. (2018) MK2 Inhibition Attenuates Fibroblast Invasion and Severe Lung Fibrosis. Am J Respir Cell Mol Biol :
Xie, Ting; Wang, Yizhou; Deng, Nan et al. (2018) Single-Cell Deconvolution of Fibroblast Heterogeneity in Mouse Pulmonary Fibrosis. Cell Rep 22:3625-3640
Xie, Ting; Liang, Jiurong; Geng, Yan et al. (2017) MicroRNA-29c Prevents Pulmonary Fibrosis by Regulating Epithelial Cell Renewal and Apoptosis. Am J Respir Cell Mol Biol 57:721-732
Liang, Jiurong; Zhang, Yanli; Xie, Ting et al. (2016) Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice. Nat Med 22:1285-1293
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
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
Liang, Jiurong; Jiang, Dianhua; Noble, Paul W (2016) Hyaluronan as a therapeutic target in human diseases. Adv Drug Deliv Rev 97:186-203
Xie, Ting; Liang, Jiurong; Liu, Ningshan et al. (2016) Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis. J Clin Invest 126:3063-79
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

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