Current Research in the Khemtong Lab
The research in our group is focused on investigating intermediary metabolism using stable isotope tracers, carbon-13, combined with magnetic resonance spectroscopy (NMR and MRI) and mass spectrometry (MS). Our goal is to gain fundamental understanding of altered substrate metabolism in diseases as well as to identify metabolic biomarkers that can be used for the early detection and treatments of metabolic diseases. We are primarily interested in non-alcoholic fatty liver disease (NAFLD), diabetes, and cancers. Our current research activities are divided into three broad areas below.
Substrate Metabolism and Flux Analysis by Carbon-13 Tracers
The main focus of our research is to investigate substrate metabolism in cultured cells, isolated perfused organs, and in vivo. We use metabolic substrates such as glucose and fatty acids enriched with carbon-13 (filled circles) at various carbon positions on the molecules of the substrates. Following the metabolism, these substrates produce downstream metabolites with different carbon-13 labeling patterns, or different isotopomers, which can be analyzed by carbon-13 nuclear magnetic resonance (NMR) and/or mass spectrometry. Fractional oxidation (through the Krebs cycle) and metabolic fluxes can be estimated from the analysis.
Metabolic Imaging with Hyperpolarized Carbon-13 MRI
In another complementing area of research, we employ hyperpolarized carbon-13 MRI to evaluate the real-time metabolism of metabolic substrates. Metabolic substrates suitable for hyperpolarized carbon-13 MRI such as pyruvate (glycolytic product of glucose) are polarized to improve carbon-13 NMR sensitivity. Metabolism of the injected substrates can be evaluated by detecting and following the downstream metabolites in organs of interest. Signal intensities of the metabolites can be used as surrogates for enzymatic conversion of the injected probe to the metabolite. Metabolic maps can also be generated from the intensities and displayed as overlays with anatomical MRI image. These hyperpolarized MRI exams can reveal areas in tissues with abnormal (increased or decreased) uptake and utilization of certain metabolic fuels.
Development of Hyperpolarized Carbon-13 Imaging Probes
Our group is also working to develop imaging probes for hyperpolarized carbon-13 applications. In this area of research, we aim to synthesize organic molecules enriched with carbon-13 isotopes for imaging abnormal cellular homeostasis such as acidification and imbalanced redox state caused by metabolic diseases. Our approach is to design molecules that are sensitive to minute changes in acidity and cellular redox. For example, we have developed a series of compounds enriched with carbon-13 that, once injected into animals, are hydrolyzed by circulating enzyme esterase to produce carbon-13 labelled carbon dioxide and bicarbonate. Ratiometric imaging of carbon-13 signals of these buffer pairs can be employed to estimate tissue pH. Other types of imaging probes are also being tested in our lab.
