Acute kidney injury 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. We contend that the combination of adjunctive image-based functional and molecular readouts of regional blood volume, oxygenation, and inflammation could enhance these new urinary biomarkers to fully quantify the renal risk state and evaluate therapy in both chronic and acute diseases. We propose to explore and compare an alternative approach to existing methods with the use of native and molecularly targeted perfluorocarbon nanoparticles (PFC NPs) that could offer numerous advantages for diagnostic imaging and drug delivery to chronic and acute kidney diseases. Our preliminary results showed intrarenal oxygenation could be non-invasively mapped by 19F MRI. Renal ischemia-reperfusion (I/R) injury induced outer medullary vascular non-perfusion was directly detected by regional reduction of 19F signal intensity from circulating PFC NPs. Such regional non-perfusion of renal vasculature was effectively inhibited by PFC NPs facilitated anticoagulation therapy. The proposal is highly translational and the methods to be developed have a direct path to clinical testing and implementation because the targeted PFC NPs contrast platform already is in FDA-approved clinical trials for molecular imaging of angiogenesis with fluorine (19F) MRI/MRS. Furthermore, the dual, simultaneous proton and fluorine imaging methods are fundamentally developed and implemented on a clinical 3T scanner, and ready for adoption by any manufacturer. Accordingly our aims are to:
AIM 1. Validate 19F MRI of PFC NPs is a quantitative measure for mapping intrarenal blood volume, PO2, and inflammation using a mouse model of renal ischemia/reperfusion (I/R) injury AIM 2. Evaluate the effect of PPACK NPs on inhibiting intrarenal nonperfusion using 19F MRI in vivo PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

Public Health Relevance

Chronic renal disease combined with acute kidney injury 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 propose to implement adjunctive noninvasive functional and molecular imaging readouts of intrarenal blood volume, oxygenation, and inflammation and to develop a nanoparticle facilitated anticoagulation therapy that should enhance diagnosis and treatment of chronic and acute kidney diseases. The proposal is highly translational and the methods to be developed have a direct path to clinical testing and implementation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK095555-02
Application #
8546379
Study Section
Special Emphasis Panel (ZRG1-SBIB-Q (04))
Program Officer
Flessner, Michael Francis
Project Start
2012-09-17
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$183,350
Indirect Cost
$62,725
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
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
Chen, Junjie; Vemuri, Chandu; Palekar, Rohun U et al. (2015) Antithrombin nanoparticles improve kidney reperfusion and protect kidney function after ischemia-reperfusion injury. Am J Physiol Renal Physiol 308:F765-73
Hou, Kirk K; Pan, Hua; Schlesinger, Paul H et al. (2015) A role for peptides in overcoming endosomal entrapment in siRNA delivery - A focus on melittin. Biotechnol Adv 33:931-40
Goette, Matthew J; Lanza, Gregory M; Caruthers, Shelton D et al. (2015) Improved quantitative (19) F MR molecular imaging with flip angle calibration and B1 -mapping compensation. J Magn Reson Imaging 42:488-94
Goette, Matthew J; Keupp, Jochen; Rahmer, Jürgen et al. (2015) Balanced UTE-SSFP for 19F MR imaging of complex spectra. Magn Reson Med 74:537-43
Palekar, Rohun U; Jallouk, Andrew P; Lanza, Gregory M et al. (2015) Molecular imaging of atherosclerosis with nanoparticle-based fluorinated MRI contrast agents. Nanomedicine (Lond) 10:1817-32
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
Hu, Lingzhi; Chen, Junjie; Yang, Xiaoxia et al. (2014) Assessing intrarenal nonperfusion and vascular leakage in acute kidney injury with multinuclear (1) H/(19) F MRI and perfluorocarbon nanoparticles. Magn Reson Med 71:2186-96

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