Idiopathic Pulmonary Fibrosis (IPF) is a scarring lung disease of unknown etiology killing over 40,000 patients each year in the US. The disease is characterized by aggregation of myofibroblasts in fibrotic foci and this lung remodeling results in poor gas exchange which is progressive and invariably fatal due to lack of treatment options. The understanding of the pathogenesis of IPF is very limited due to lack of good assay systems replicating the disease as well as lack of good model systems to study drug efficacy. We have generated a novel, robust, clinically relevant human model for IPF using induced pluripotent stem cells (iPSCs) from IPF patients. Specifically, this model lends itself to drug discovery as the patient derived iPSCs develop progressive fibrotic foci in the dish when redifferentiated to mesenchymal-type cells, thereby recapitulating the disease phenotype in a dish.
Our Specific Aims are: 1. We will develop a high throughput screening (HTS) assay to identify small molecule probes for target discovery and validation, test already approved drugs for repurposing as IPF treatment and add new compounds for IPF drug development utilizing our disease in a dish model. Our in vitro model displays a striking resemblance to the fibrotic foci seen in the IPF fibrotic phenotype in the clinic - including apoptosis-resistant, hyperproliferative fibroblasts an exaggerated extracellular matrix accumulation. The assay will be validated with tool compounds and functional genomics probes available at the Molecular Screening Shared Resource at UCLA. 2. We will subject our disease model to a phenotype-based small molecule primary pilot HTS screen with high content screening (HCS) as readout. HCS is the ideal tool for assessing the activity of small molecules in this context as the disease modifying targets of IPF are unknown but the changes in cell morphology from the diseased to healthy state are very obvious. 3. We will perform hit validation, secondary assays/hit triaging and characterization through counterscreening, toxicity testing and functional genomics such as lentiviral shRNA gene knockdown and cDNA complementation strategies.
We aim to identify novel small molecule probes, approved drugs and new small molecules that target the abnormal tissue remodeling of IPF, which is characterized by excessive extracellular matrix accumulation. Thus this proposal aims to advance the diagnosis, treatment and prevention of the disease of IPF and is therefore fully aligned with the goals of the NIGMS.

Public Health Relevance

Idiopathic Pulmonary Fibrosis (IPF) is a complex and incurable disease that kills about 40,000 people in the US alone each year. We have generated a novel model of IPF which is based on patient tissue and will use it to screen thousands of compounds to identify novel compounds to treat IPF. We will validate the compounds identified with additional screening and testing on patient samples.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Fabian, Miles
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Wilkinson, Dan C; Mellody, Michael; Meneses, Luisa K et al. (2018) Development of a Three-Dimensional Bioengineering Technology to Generate Lung Tissue for Personalized Disease Modeling. Curr Protoc Stem Cell Biol 46:e56
Sucre, Jennifer M S; Vijayaraj, Preethi; Aros, Cody J et al. (2017) Posttranslational modification of ?-catenin is associated with pathogenic fibroblastic changes in bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 312:L186-L195
Wilkinson, Dan C; Alva-Ornelas, Jackelyn A; Sucre, Jennifer M S et al. (2017) Development of a Three-Dimensional Bioengineering Technology to Generate Lung Tissue for Personalized Disease Modeling. Stem Cells Transl Med 6:622-633
Sucre, Jennifer M S; Wilkinson, Dan; Vijayaraj, Preethi et al. (2016) A three-dimensional human model of the fibroblast activation that accompanies bronchopulmonary dysplasia identifies Notch-mediated pathophysiology. Am J Physiol Lung Cell Mol Physiol 310:L889-98