Abnormalities in mitochondrial metabolism including redox state have been identified under many pathological conditions including cancer, diabetes, aging, and cardiovascular disease. Mitochondrial NAD (nicotinamide adenine dinucleotide)-coupled redox potential NAD+/NADH regulates a number of oxidation-reduction reactions in metabolism, and also mediates key signaling events important for cell growth, survival and apoptosis. There is a great need for a non-invasive method of quantifying and/or measuring mitochondrial NAD+/NADH redox potential in tissues in vivo for the purpose of developing effective approaches for disease diagnosis and treatment. In this project we will develop and validate a clinically translatable and non-invasive hyperpolarized-carbon-13 magnetic resonance spectroscopic imaging (HP-13C-MRSI) method for imaging the mitochondrial redox potential NAD+/NADH in vivo using breast cancer animal models. HP-13C-MR is over 10,000 times more sensitive than conventional MR and has been used to image tissue metabolism. The rationale is to quantify the NAD-coupled redox potential using the equilibrium constant for an enzymatic reaction in mitochondria only, i.e., -hydroxybutyrate + NAD+ ` acetoacetate + NADH + H+, provided that the ratios of acetoacetate/- hydroxybutyrate and the mitochondrial pH can be quantified by MR methods. The proposed method is specific for the NAD+/NADH couple in mitochondria. We will also propose to use 13C-labeled ester probes (e.g. ethyl- hydroxybutyrate) to differentiate between extracellular and intracellular MR signals to obtain the redox potential with higher accuracy. Since our previous studies using cryogenic NADH/flavoprotein fluorescence imaging ex vivo have linked mitochondrial redox state to the metastatic potential of human melanoma and breast cancer in mouse xenografts, this project will also establish a correlation between mitochondrial NAD+/NADH and the metastatic potential of breast cancer, which supports mitochondrial redox potential as a biomarker for cancer diagnosis and treatment response, and a target for therapy. We will investigate whether the mitochondrial redox potential NAD+/NADH measured by the HP-13C-MR method can differentiate an indolent (MCF-7) and a highly metastatic (MDA-MB-231) breast cancer cell line. We will perform redox potential measurements on perfused cell models and mouse xenografts under different mitochondrial metabolic conditions and correlate the results with biochemical assays. We will also validate the techniques on human patients with low or high grade breast tumors to demonstrate its clinical translatability.
Imaging mitochondrial redox states in vivo by hyperpolarized MR Project Summary/Abstract: This proposal is to develop a clinical translatable non-invasive hyperpolarized-carbon-13 magnetic resonance imaging method for quantifying the mitochondrial redox potential NAD+/NADH in vivo in breast tumors. The successful development of the technique will have broad applications in many diseases identified with metabolic abnormalities including cancers, diabetes and cardiovascular diseases. This project may also establish the mitochondrial redox state as a biomarker for cancer diagnosis and treatment response, and a target for therapy.
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|Moon, Lily; Frederick, David W; Baur, Joseph A et al. (2017) Imaging Redox State in Mouse Muscles of Different Ages. Adv Exp Med Biol 977:51-57|
|Xu, He N; Kadlececk, Stephen; Shaghaghi, Hoora et al. (2016) Differentiating inflamed and normal lungs by the apparent reaction rate constants of lactate dehydrogenase probed by hyperpolarized (13)C labeled pyruvate. Quant Imaging Med Surg 6:57-66|
|Xu, He N; Tchou, Julia; Feng, Min et al. (2016) Optical redox imaging indices discriminate human breast cancer from normal tissues. J Biomed Opt 21:114003|
|Sun, Nannan; Xu, He N; Luo, Qingming et al. (2016) Potential Indexing of the Invasiveness of Breast Cancer Cells by Mitochondrial Redox Ratios. Adv Exp Med Biol 923:121-127|
|Li, Lin Z (2016) A pre-tracer approach for improving the accuracy of metabolic measurements by hyperpolarized nuclear magnetic resonance. Quant Imaging Med Surg 6:612-614|
|Tain, Rongwen; Xu, He N; Zhou, Xiaohong J et al. (2016) Magnetization Transfer MRI Contrast May Correlate with Tissue Redox State in Prostate Cancer. Adv Exp Med Biol 923:401-406|
|Cai, Kejia; Xu, He N; Singh, Anup et al. (2014) Breast cancer redox heterogeneity detectable with chemical exchange saturation transfer (CEST) MRI. Mol Imaging Biol 16:670-9|
|Xu, He N; Kadlececk, Stephen; Profka, Harrilla et al. (2014) Is higher lactate an indicator of tumor metastatic risk? A pilot MRS study using hyperpolarized (13)C-pyruvate. Acad Radiol 21:223-31|
|Xu, He N; Tchou, Julia; Li, Lin Z (2013) Redox imaging of human breast cancer core biopsies: a preliminary investigation. Acad Radiol 20:764-8|
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