Next Generation Hyperpolarized Magnetic Resonance Imaging with [U-2H, 3-13C]Fructose for Staging Diet-Induced Liver Disease - Project Summary/Abstract More than 33% of yearly deaths in the US have been attributed to hepatic metabolic dysfunctions fueled by high dietary fructose. While dietary intervention and therapeutic advancements can reduce disease burden, early detection and accurate staging are imperative for therapeutic efficacy and patient survival. Furthermore, as conventional diagnostics like elastography, biopsy, and blood work analysis face limitations in their specificity, sensitivity, and safety, advancements in liver disease diagnostics are urgently needed. Existing imaging approaches can be improved by developing safe, noninvasive methods for enhanced metabolic contrast. The liver is a major fructolytic organ that can be rewired by aberrant disease metabolism. Therefore, imaging fructose metabolism in the liver may reveal novel insights into the mechanistic basis of disease. Recent advancements have achieved in vivo metabolic contrast with [6,6’-2H2]fructose DMI and [U-2H, 2-13C]fructose HP MRI, but are limited by either bolus dosing or insensitivity to glycolytic activity, which could be leveraged to generate a comprehensive readout of multiple products. The overall goal of this research is to develop an HP MRI method to assess differential [1-13C]lactate production from [U-2H, 3-13C]fructose as a marker of liver metabolism and to stage diet-induced liver disease. Based on promising preliminary data, I hypothesize that lactate will generate metabolic contrast and allow for accurate staging. Two aims will test this hypothesis. Aim 1 will generate optimized protocols for synthesizing and polarizing [U-2H, 3-13C]fructose to maximize sensitivity and signal. Aim 2 will test preliminary and optimized methods by staging and monitoring a HFSW diet-induced model of liver disease by imaging lactate production and correlating results to clinical markers of disease. Building upon strong preliminary imaging data, these aims will utilize HP MRI, NMR, mass spectrometry (MS), isotope tracing, metabolic flux modeling, and metabolomics. Ultimately, this research will generate widely relevant knowledge on metabolism and imaging, along with a novel imaging method suitable for other disease models and circumstances in which a fructolytic or glycolytic disturbance is suspected. My rigorous, reproducible research plans — including thorough training in metabolism, hyperpolarization, MRI, NMR, isotope tracer analysis, MS, metabolomics, and literature analysis — will prepare me for an independent Principal Investigator position at a Tier 1 research institute. My comprehensive training plan will offer multifold opportunities to enhance my laboratory techniques, networking, scientific communication, and mentorship. All this will occur in the outstanding research environment provided by Dr. Kayvan Keshari’s laboratory and several MSK-sponsored interdisciplinary research cores.
