“3D High Throughput Model to Predict Drug Efficacy in Fibrosis Progression vs Reversal”
Although two drugs have recently gained FDA-approval for IPF, these drugs only moderately slow the progression of lung decline and do not improve quality of life for patients. There are no available therapies that can ‘reverse’ fibrosis. This proposal integrates expertise in fibroblast aging and novel IPF therapeutics in development (Hecker lab) with cutting edge technologies for microscale bioprinting and 3D cell assays (Takayama lab) to bioengineer a high-throughput phenotypic assay that will evaluate fibrosis over a 21 day period. The proposed model will enable the first high-throughput phenotypic screening assay with the capability to determine a drug candidate’s efficacy for fibrosis progression and reversal.
MPI: Hecker, MPI: Takayama
UA Sarver Heart Center
“Role of Nox4 in Duchenne Muscular Dystrophy-related Dileted Cardiomyopathy”
The major goal of this project is to develop a double-knockout mouse model of dystrophin and Nox4 as a research tool for validation of Nox4 as a target for therapy in Duchenne muscular dystrophy-related dilated cardiomyopathy and cardiac fibrosis.
Co-I: Hecker, PI: Colson
Department of Defense (W81XWH-17-1-0443)
“Pre-clinical development of small-molecule inhibitors targeting Nox4 for the treatment of pulmonary fibrosis”
This project will continue the pre-clinical development of previously identified small-molecule inhibitors targeting Nox4 including lead optimization through medicinal chemistry efforts, efficacy validation utilizing the most rigorous cell and animal models, and evaluate toxicology profiles in rats and beagles in order to determine the no observed effects level (NOEL) dose. The overall goal of this study is to identify a therapeutic product and protocol that will advance to GLP-IND enabling toxicity studies (required for Phase I human clinical trials).
Department of Veterans Affairs (BX003919)
“The role of Nampt in age-associated persistent lung fibrosis”
The mechanisms that drive continued propagation of fibrogenic responses, beyond initial injury, remain poorly understood. These studies will evaluate a novel auto-regulatory mechanism (eNampt/iNampt) in the temporal reinforcement of pro-fibrotic responses in age-dependent pathological fibrosis. These studies also evaluate the pre-clinical efficacy of FK-866 (iNampt inhibitor in clinical trials as an anti-cancer agent) in rigorous aging animal models of fibrosis, enhancing the potential for rapid clinical translation of novel therapeutics for IPF.
“Pre-clinical development of a novel Nrf2-activator formulation for the treatment of idiopathic pulmonary fibrosis”
Dimethyl fumarate (DMF) is an Nrf2 activator that is FDA-approved the treatment of multiple sclerosis via oral delivery. The goal of this project is to evaluate the efficacy of DMF via oral versus inhaled (local) routes of administration for a new indication, pulmonary fibrosis. These studies utilize a novel DMF formulation for efficacy testing in an aged mouse model of persistent fibrosis. This approach may provide a first-in-class therapeutic platform for the treatment of IPF in a targeted manner.
MPI: Hecker, MPI: Mansour
“Novel Targeting of the S1P Receptor, S1P1, and Nox4 as Therapeutic Approaches in ARDS”
The goal of this project is to continue the pre-clinical development for novel treatment strategies for acute respiratory distress syndrome (ARDS)
PI: Hecker, PI: Garcia
“Pre-clinical efficacy of Nintedanib in an aging model of persistent lung fibrosis.”
The goal of this project is to evaluate the pre-clinical efficacy of Nintedanib, an FDA-approved therapeutic for IPF, in a more rigorous animal model. These studies will utilize an aging mouse model of persistent lung fibrosis to determine the efficacy of Nintedanib in ameliorating age-associated established fibrosis.
Arizona Dept. of Health Services (ADHS17-00007403)
AZ investigator grant
"A Novel Ex-vivo Leaf-lung model to Study Pulmonary Diseases"
There is a desperate need for more sophisticated ex-vivo lung models. The goal of this project is to utilize decellularized leaf to recapitulate the lung endothelial-epithelial micro-environment, which will stimulate the gas exchange surface of the air sac. The proposed "Lung on a Leaf" model will provide a platform to study cell-cell interactions in a 3-D context and granulomatous immunological responses, will be widely applicable to other diseases, and has the capacity to accelerate testing of therapeutic molecules in a more biologically relevant system.
Co-I: Hecker; PI: Knox