Oxygen free radicals and nitric oxide are central mediators of cellular injury in a variety of disease processes including: ischemia/reperfusion injury (following heart attack, stroke, cardio-pulmonary resuscitation, or organ transplantation); septic shock; cancer; and aging. In view of this importance, there has been a great need for methods enabling in vivo measurement and imaging of free radicals in animal models of disease. Our laboratory and others have shown that EPR imaging is a powerful technique that enables three-dimensional spatial mapping of free radical metabolism, oxygenation, and nitric oxide with submillimeter resolution. We have previously developed instrumentation of EPR spectroscopy and imaging at 1-2 GHz using a standard iron core electromagnet that has enabled imaging of free radicals in isolated organs and small mice. However, to extend this promising new technology for the goal of studying disease processes in commonly used in vivo animal models such as rats and rabbits, new instrumentation must be developed to accommodate these mach larger with lower frequency suitable to penetrate their large volumes. In this proposal there are a series of specific aims that provide the critical developments necessary to achieve this goal. These include: I. Development and optimization of a new type of air-core magnet and magnetic field gradient system with a much larger free gap (>12 cm) while maintaining maximum gradient strength and linearity; II. Development of a 300 MHz radio-frequency bridge for maximum sensitivity on large in vivo samples with provisions to minimize noise from motion or other sources; III. Development of optimized resonators at 300 MHz for maximum sensitivity and stability for in vivo biomedical applications with automatic tuning and automatic coupling capability; IV. Development of optimized software for instrument control, image acquisition, reconstruction and analysis, with provisions to enable rapid image data collection and co-mapping of anatomic structure and free radical distribution. These developments and innovations will result in development of a new type of EPR imaging instrument optimized for in vivo measurement and imaging of free radicals, oxygen, and nitric oxide in a variety of important animal models of disease.
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