Development of a High-Throughput Screen for Pre-therapeutic Discovery in Idiopathic Pulmonary Fibrosis

University Of California Los Angeles, Los Angeles CA

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Abstract

? DESCRIPTION (provided by applicant): 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.