Paramagnetic molecules including oxygen, oxygen radicals and nitric oxide modulate cellular function and injury, altering critical cellular processs such as respiration and redox state with changes in tissue perfusion, energetic state and viability. In view of the critical importance of these interactions in normal cardiovascular functin and disease, there has been a great need for an approach to combine in vivo measurement and imaging of paramagnetic molecules with imaging of tissue and organ biochemical and functional parameters in animal models of disease. EPR imaging (EPRI) is a powerful technique that enables 3D spatial in vivo mapping of radical metabolism, oxygenation, and nitric oxide;however, the utility and power of EPRI has been greatly limited by the need for complementary anatomic and functional data. NMR based MRI, in addition to providing anatomic registration, also can provide critical functional information that is needed to interpret the EPRI data including, imaging of tissue perfusion and viability. Integrated EPR/NMR imaging technology and instrumentation has the unique potential to enable in vivo mapping of free radicals, oxygen and nitric oxide along with NMR based functional and anatomic imaging. This technology is very promising but several fundamental problems presently limit its development and biomedical application. These include the need to: [a] provide seamless integration of the EPR and NMR-MRI systems to enable rapid transition between these two imaging modalities;[b] build dual mode resonators optimized for both EPR and NMR resonances suited for specific biomedical applications;[c] accelerate the process of image data collection in both modes facilitating dual mode anatomic and functional imaging;[d] increase sensitivity and minimize motion-induced noise or image distortion;[e] integrate the EPRI and MRI results and analysis in order to perform accurate image co-registration, fast computation and interpretation of functional data. These critical needs will be addressed with a combination of hardware and software development followed by testing in cardiovascular applications as described in 3 specific aims: I. Development and construction of EPRI hardware optimized for high sensitivity fast scan image acquisition and integration of it with high field MRI;II. Development / implementation of integrated software and algorithms for fast EPRI and NMR MRI acquisition with cardiac gating enabling co-mapping of anatomic structure, perfusion, energetic state and viability (MRI) with free radical distribution, redox state and oximetry (EPRI). EPRI acquisition will be accelerated and refined using NMR image information to refine EPR data collection;III. Application for dual mode functional imaging of the heart with both in vivo and ex vivo measurement of tissue O2 levels, redox status, nitric oxide formation (EPRI) in relation to perfusion, viability, and energeic state (MRI). This program will realize the great synergy and power of integrated real time EPRI and high field MRI optimized for biomedical measurement and imaging of free radicals, redox state, O2, and nitric oxide and their role in function and disease.
Oxygen, oxygen free radicals and nitric oxide are critical mediators of cardiovascular function and injury of central importance in disease. We will develop unique instrumentation that integrates the combined strengths of state of the art electron and nuclear magnetic resonance imaging to understand normal heart function as well as the mechanisms of heart disease and how it can be ameliorated or prevented.
|Velayutham, Murugesan; Hemann, Craig F; Cardounel, Arturo J et al. (2016) Sulfite Oxidase Activity of Cytochrome c: Role of Hydrogen Peroxide. Biochem Biophys Rep 5:96-104|
|Driesschaert, Benoit; Bobko, Andrey A; Eubank, Timothy D et al. (2016) Poly-arginine conjugated triarylmethyl radical as intracellular spin label. Bioorg Med Chem Lett 26:1742-4|
|Dhimitruka, Ilirian; Alzarie, Yasmin Alsayed; Hemann, Craig et al. (2016) Trityl radicals in perfluorocarbon emulsions as stable, sensitive, and biocompatible oximetry probes. Bioorg Med Chem Lett 26:5685-5688|
|Ahmad, Rizwan; Samouilov, Alexandre; Zweier, Jay L (2016) Accelerated dynamic EPR imaging using fast acquisition and compressive recovery. J Magn Reson 273:105-112|
|Tan, Xiaoli; Song, Yuguang; Liu, Huiqiang et al. (2016) Supramolecular host-guest interaction of trityl-nitroxide biradicals with cyclodextrins: modulation of spin-spin interaction and redox sensitivity. Org Biomol Chem 14:1694-701|
|Driesschaert, Benoit; Bobko, Andrey A; Khramtsov, Valery V et al. (2016) Nitro-Triarylmethyl Radical as Dual Oxygen and Superoxide Probe. Cell Biochem Biophys :|
|Mathies, Guinevere; Caporini, Marc A; Michaelis, Vladimir K et al. (2015) Efficient Dynamic Nuclear Polarization at 800 MHz/527 GHz with Trityl-Nitroxide Biradicals. Angew Chem Int Ed Engl 54:11770-4|
|Winner 3rd, Marshall W; Sharkey-Toppen, Travis; Zhang, Xiaolan et al. (2015) Iron and noncontrast magnetic resonance T2* as a marker of intraplaque iron in human atherosclerosis. J Vasc Surg 61:1556-64|
|Xie, Lin; Talukder, M A Hassan; Sun, Jian et al. (2015) Liposomal tetrahydrobiopterin preserves eNOS coupling in the post-ischemic heart conferring in vivo cardioprotection. J Mol Cell Cardiol 86:14-22|
|Reyes, Levy A; Boslett, James; Varadharaj, Saradhadevi et al. (2015) Depletion of NADP(H) due to CD38 activation triggers endothelial dysfunction in the postischemic heart. Proc Natl Acad Sci U S A 112:11648-53|
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