Prevention and Treatment of Acute Kidney Injury

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 DESCRIPTION (provided by applicant): Acute kidney injury (AKI) in the face of chronic kidney disease is a frequent clinical problem with an increasing incidence, an unacceptably high mortality rate that has not improved in more than 50 years, and no specific treatment. Interest is keen for the pursuit of methods for quantifying structural and functional disruption in progressive chronic disease and acute injury that might improve the sensitivity, specificity, and time in which renal injury is diagnosed, and facilitate risk stratification and/or provide prognostic information including prediction of recovery of renal function. Furthermore, novel therapeutic strategies are needed to meet the medical need for both safe and effective preventative and post-injury applications in AKI. We have recently proposed and evaluated new image based methods for mapping intrarenal blood volume and PO2 on a voxel- wise basis with perfluorocarbon nanoparticle contrast agents employing fluorine (19F) imaging and spectroscopy. We also have discovered new highly specific biomarkers of proximal tubular injury (myo-Inositol Oxygenase: MIOx) that can be applied for early detection and management of AKI. We now seek to define the potential broader translational utility of these tools as objective, noninvasive, quantitative approaches for assessing renal inflammation, coagulation, and hypoxia over time and space in animal models. The rationale for these efforts emerges from growing evidence that interactions among inflammatory and coagulation pathways play a pivotal role in AKI. Such vascular damage not only causes an overall reduction of renal blood flow that compromises glomerular filtration but also leads to regional perfusion deficits, extended hypoxic/ischemic injury, necrosi, and apoptosis that impair tubular cell regeneration and repair. We will design and deploy new nanoparticle therapeutic agents that are active against selected inflammatory signaling pathways (e.g., NF¿B, apoptosis: Bak/Bax, and thrombin/PAR-1) in unique and effective formulations that provide localized sustained release of agents (peptides, siRNA) that may be complementary and synergistic in early and advanced AKI, or even when applied as preventative measures. Accordingly our aims are to: AIM 1. Deploy selected and synergistic nanoparticle agents singly and in combination against promising molecular targets in AKI (NFkB, thrombin, Bak/Bax) and define efficacy for early and late AKI, and as preventive agents in a mouse model of renal ischemia/reperfusion (I/R) injury. AIM 2. Apply dual 1H/19F MRI and spectroscopy of PFC NP in vivo to quantify intrarenal blood volume, PO2, and inflammation in injured kidneys over time, and delineate responses to nanotherapies, in concert with new biomarkers specific for proximal tubular damage (MIOx).