Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Biochemistry & Molecular Biophysics

First Advisor

Ravinder Reddy

Abstract

Oxidative phosphorylation (OXPHOS) and glycolysis are two cellular metabolic pathways that play a crucial role in the functions of biological systems. Currently, magnetic resonance spectroscopy (MRS) (13C, 31P, and 1H) and positron emission tomography (PET) methods are used to investigate changes in these pathways that result from metabolic dysfunction. However, MRS methods are limited by low resolution and long acquisition times. While 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET is a widely used clinical modality, it requires the use of radioactive ligands. Thus, there is an unmet need for techniques to image these metabolic processes noninvasively, and with higher resolution in vivo. In this dissertation, we exploited the chemical exchange saturation (CEST) phenomenon to develop and optimize endogenous CEST magnetic resonance imaging (MRI) methods to measure OXPHOS and glycolysis, and demonstrated application of those techniques to study impaired metabolism in vivo. These CEST methods offer several orders of magnitude higher sensitivity compared to traditional spectroscopic techniques. Recently developed CEST imaging of free creatine (CrCEST) was targeted as a means of measuring OXPHOS. We optimized and validated this technique in healthy human skeletal muscle, showing that CrCEST imaging in dynamic exercise studies provides a measure of the mitochondrial rate of OXPHOS. CrCEST imaging was then implemented in a cohort of subjects affected by genetic disorders of the mitochondria. The results of these studies demonstrate that CrCEST has the capability to distinguish between healthy and impaired OXPHOS in muscle. In some diseases with altered metabolism, like cancer, aerobic glycolysis dominates, leading to increased lactate production. Existing methods for imaging lactate in vivo involve expensive, radiolabeled tracers. In this work, we demonstrated the feasibility of imaging lactate with CEST (“LATEST”) in phantoms with physiological concentrations. Then, we validated the method dynamically in vivo by measuring lactate production and clearance in intensely exercised human skeletal muscle, which utilizes anaerobic glycolysis. Finally, we infused rats bearing lymphoma tumors with non-labeled pyruvate and demonstrated the ability of LATEST MRI to image tumors and measure dynamic lactate changes over time. Together, these studies demonstrate that metabolic processes can be monitored in vivo using CEST MRI, with potential for widespread clinical applications.

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