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., NFB, 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).

Public Health Relevance

Acute kidney injury (AKI) 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. We have recently proposed and evaluated new image based methods for mapping intrarenal blood volume and PO2 with perfluorocarbon nanoparticle contrast agents employing fluorine (19F) imaging and spectroscopy. We will design and deploy new nanoparticle therapeutic agents that are active against selected inflammatory signaling pathways in unique and effective formulations that provide localized sustained release of agents that may be synergistic in early and advanced AKI, and whose effects on kidney cells can be mapped over time with safe, noninvasive imaging tools.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK102691-05
Application #
9528289
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Chan, Kevin E
Project Start
2016-12-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of South Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Vemuri, Chandu; Upadhya, Gundumi A; Arif, Batool et al. (2018) Antithrombin Perfluorocarbon Nanoparticles Improve Renal Allograft Function in a Murine Deceased Criteria Donor Model. Transplant Direct 4:e384
Moore, Jeremy K; Chen, Junjie; Pan, Hua et al. (2018) Quantification of vascular damage in acute kidney injury with fluorine magnetic resonance imaging and spectroscopy. Magn Reson Med 79:3144-3153
Kabir, Ashraf Ul; Lee, Tae-Jin; Pan, Hua et al. (2018) Requisite endothelial reactivation and effective siRNA nanoparticle targeting of Etv2/Er71 in tumor angiogenesis. JCI Insight 3:
Yan, Huimin; Duan, Xin; Pan, Hua et al. (2016) Suppression of NF-?B activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc Natl Acad Sci U S A 113:E6199-E6208
Palekar, Rohun U; Jallouk, Andrew P; Myerson, Jacob W et al. (2016) Inhibition of Thrombin With PPACK-Nanoparticles Restores Disrupted Endothelial Barriers and Attenuates Thrombotic Risk in Experimental Atherosclerosis. Arterioscler Thromb Vasc Biol 36:446-55
Palekar, Rohun U; Vemuri, Chandu; Marsh, Jon N et al. (2016) Antithrombin nanoparticles inhibit stent thrombosis in ex vivo static and flow models. J Vasc Surg 64:1459-1467
Esser, Alison K; Schmieder, Anne H; Ross, Michael H et al. (2016) Dual-therapy with ?v?3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model. Nanomedicine 12:201-11
Jallouk, Andrew P; Palekar, Rohun U; Pan, Hua et al. (2015) Modifications of natural peptides for nanoparticle and drug design. Adv Protein Chem Struct Biol 98:57-91
Hughes, Michael S; McCarthy, John E; Bruillard, Paul J et al. (2015) Entropy vs. Energy Waveform Processing: A Comparison Based on the Heat Equation. Entropy (Basel) 17:3518-3551
Palekar, Rohun U; Jallouk, Andrew P; Goette, Matthew J et al. (2015) Quantifying progression and regression of thrombotic risk in experimental atherosclerosis. FASEB J 29:3100-9

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