Existing clinical markers for early renal disease are very limited. Better monitoring and management of renal disease is a pressing unmet medical need. The overall goal of this project is to develop the application of new hyperpolarized carbon-13 (13C) MRI technology for monitoring renal disease. In addition to the candidate's research plan, this application for a NIDDK Mentored Research Scientist Development Award (K01) also includes a mentored career development plan for Dr. Cornelius von Morze to achieve his ultimate career goals as an independent investigator. This resubmission application contains enhanced multi-disciplinary research and training plans for improved scientific and clinical impact. Dr. von Morze will investigate new contrast mechanisms based on novel hyperpolarized (HP) 13C MR molecular imaging contrast agents to probe key renal transport and metabolic processes in preclinical models. HP urea imaging, co-polarized and imaged simultaneously with a reference tracer, will be applied to probe renal urea transport with high specificity. HP urea imaging will be applied to monitor clinically significant altered states of urea transport: progressive renal damage associated with NSAID use, and novel urearetic drug- induced diuresis. Molecular imaging of HP lactic acid will be investigated as a novel probe of renal gluconeogenesis, a crucial contributor to glucose homeostasis in the fasting state which is dramatically and selectively dysregulated in type 2 diabetes mellitus. These imaging studies will allow highly novel characterization of renal disease in preclinical murine models.
This research aims to improve monitoring and management of renal disease with the potential for clinical translation due to the noninvasiveness, safety, and feasibility of these new molecular MR imaging methods. Dr. Cornelius von Morze's graduate work focused on advanced MRI technique development and his postdoctoral research has resulted in new technical development and applications of novel HP 13C MR molecular imaging contrast agents, particularly for renal imaging. The mentored career development plan described in this proposal will expand Dr. von Morze's breadth of knowledge with theoretical and experimental experience in preclinical models, renal physiology, biological assays and histology. He will also improve his skills for hypothesis-driven research and in laboratory management. This NIDDK K01 project has been designed to enable his long-term goal of leading world-class independent university research in MR molecular imaging of renal disease for the study of both experimental disease models and ultimately patients to address currently unmet clinical needs.

Public Health Relevance

Prevalence of chronic renal disease has increased dramatically in recent years, and is projected to increase much further over the next decade. Better management of renal disease is a pressing unmet medical need. The proposed project could result in new noninvasive ways to monitor early renal disease, better understanding of the factors that lead to progression of renal disease, and the evaluation of new treatments to prevent its progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
7K01DK099451-06
Application #
9846690
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2019-02-01
Budget End
2019-03-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
von Morze, Cornelius; Ohliger, Michael A; Marco-Rius, Irene et al. (2018) Direct assessment of renal mitochondrial redox state using hyperpolarized 13 C-acetoacetate. Magn Reson Med 79:1862-1869
von Morze, Cornelius; Merritt, Matthew E (2018) Cancer in the crosshairs: targeting cancer metabolism with hyperpolarized carbon-13 MRI technology. NMR Biomed :e3937
von Morze, Cornelius (2018) Detecting liver injury non-invasively using hyperpolarized 13 C MRI. Liver Int 38:988-990
Morze, Cornelius von; Allu, Prasanna K R; Chang, Gene Y et al. (2018) Non-invasive detection of divergent metabolic signals in insulin deficiency vs. insulin resistance in vivo. Sci Rep 8:2088
Milshteyn, Eugene; von Morze, Cornelius; Reed, Galen D et al. (2018) Using a local low rank plus sparse reconstruction to accelerate dynamic hyperpolarized 13C imaging using the bSSFP sequence. J Magn Reson 290:46-59
Milshteyn, Eugene; von Morze, Cornelius; Gordon, Jeremy W et al. (2018) High spatiotemporal resolution bSSFP imaging of hyperpolarized [1-13 C]pyruvate and [1-13 C]lactate with spectral suppression of alanine and pyruvate-hydrate. Magn Reson Med 80:1048-1060
von Morze, Cornelius; Reed, Galen D; Larson, Peder E et al. (2018) In vivo hyperpolarization transfer in a clinical MRI scanner. Magn Reson Med 80:480-487
von Morze, Cornelius; Tropp, James; Chen, Albert P et al. (2018) Sensitivity enhancement for detection of hyperpolarized 13 C MRI probes with 1 H spin coupling introduced by enzymatic transformation in vivo. Magn Reson Med 80:36-41
Shang, Hong; Sukumar, Subramaniam; von Morze, Cornelius et al. (2017) Spectrally selective three-dimensional dynamic balanced steady-state free precession for hyperpolarized C-13 metabolic imaging with spectrally selective radiofrequency pulses. Magn Reson Med 78:963-975
von Morze, Cornelius; Chang, Gene-Yuan; Larson, Peder E Z et al. (2017) Detection of localized changes in the metabolism of hyperpolarized gluconeogenic precursors13C-lactate and13C-pyruvate in kidney and liver. Magn Reson Med 77:1429-1437

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