Pilot 12: Identification of Biomarkers for Cystic Fibrosis Associated Nephrotoxicity

P.I.: Neal Paragas, PhD
Research Assistant Professor,
Medicine (Nephrology)

There are currently no biomarkers in use that guide the safe use of the powerful and effective therapeutics used in cystic fibrosis (CF). A significant lesion remains in the identification of acute kidney injury, the initiation and progression of kidney disease prior to elevation of standard clinical indicators such as serum creatinine. This project plans to reveal the timing of the novel kidney injury biomarker neutrophil gelatinase associated lipocalin (NGAL) and map the cell specific expression of other novel renal injury biomarkers in response to known nephrotoxic therapeutics used to treat related cystic fibrosis illnesses. Early identification of nephrotoxic stress which ultimately leads to dysregulation and activation of injury pathways will inform the clinician in therapeutic dosing strategies and identify which therapeutics to use because of heterogeneous sensitivities. To illuminate this process of hidden renal injury to the commonly used aminoglycoside antibiotic gentamicin: (i) use a non-invasive animal model to test the dose responsiveness and sensitivity of the NGAL-reporter mouse; (ii) use of a tissue specific RNA-isolation system to identify pathways and novel secreted molecules for biomarker development. Additionally, this system will also significantly reduce animal usage and time of experimentation because it utilizes optical imaging and RNA-isolation technologies that inherently require less animal usage. Ultimately, defining early stages of nephrotoxic stress in CF patients is of great significance to the millions of children who suffer from CF related diseases and require a lifetime of exposure to potentially nephrotoxic therapies.