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.
|Takahashi, Wataru; Bobko, Andrey A; Dhimitruka, Ilirian et al. (2014) Proton-Electron Double-Resonance Imaging of pH using phosphonated trityl probe. Appl Magn Reson 45:817-826|
|Moldovan, Nicanor I; Anghelina, Mirela; Varadharaj, Saradhadevi et al. (2014) Reoxygenation-derived toxic reactive oxygen/nitrogen species modulate the contribution of bone marrow progenitor cells to remodeling after myocardial infarction. J Am Heart Assoc 3:e000471|
|Tong, Jianjing; Zweier, Joseph R; Huskey, Rachael L et al. (2014) Effect of temperature, pH and heme ligands on the reduction of Cygb(Fe(3+)) by ascorbate. Arch Biochem Biophys 554:1-5|
|Chen, Yeong-Renn; Zweier, Jay L (2014) Cardiac mitochondria and reactive oxygen species generation. Circ Res 114:524-37|
|Samouilov, Alexandre; Efimova, Olga V; Bobko, Andrey A et al. (2014) In vivo proton-electron double-resonance imaging of extracellular tumor pH using an advanced nitroxide probe. Anal Chem 86:1045-52|
|De Pascali, Francesco; Hemann, Craig; Samons, Kindra et al. (2014) Hypoxia and reoxygenation induce endothelial nitric oxide synthase uncoupling in endothelial cells through tetrahydrobiopterin depletion and S-glutathionylation. Biochemistry 53:3679-88|
|Bobko, Andrey A; Dhimitruka, Ilirian; Zweier, Jay L et al. (2014) Fourier transform EPR spectroscopy of trityl radicals for multifunctional assessment of chemical microenvironment. Angew Chem Int Ed Engl 53:2735-8|