Reactive oxygen species (ROS) are important mediators in the pathogenesis of a wide range of diseases such as cancer, neurocognitive and neurodenerative disorders, and diabetes mellitus. Moreover, oxidative stress secondary to increased ROS is central to pathogenesis various cardiovascular diseases including arteriosclerosis, hypertension, and heart failure. ROS include the free radical superoxide anion ,which initiates the production of other free radical species. When ROS production surpasses cellular defensive mechanisms it interacts with DNA causing mutations, proteins causing defects or dysfunctional enzymes, and lipids causing damage to cellular membranes. In light of the central role superoxide in the pathophysiology of disease, the objective of this proposal is to develop a PET radiotracer that will permit the noninvasive measurement of oxidative stress, in particular in cardiovascular disease. To meet this goal, we will employ a research design composed of two Specific Aims that are performed in parallel but converge by the end of grant.
In Specific Aim 1 (SA 1), we will develop and validate a PET imaging approach to measure myocardial superoxide anion levels as an indicator of oxidative stress. In doing so, we will synthesize F-labeled methoxyanalogs of dihydroethidium (F-DHE) analogs for imaging superoxide levels, screen analogs through in-vitro assays, perform metabolite analysis of select optimal agents, and validate the F-DHE analog in 2 animal models adriamycin-induced ROS and a physiological model based on results from Specific Aim 2-by correlation to optical and confocal microscopy measurements.
In Specific Aim 2 (SA2), we will delineate the relationship between the gender, myocardial FA metabolism and ROS production in the pathological progression of cardiomyopathy in a rodent model of type-2 diabetes mellitus . We will manipulate the dynamic range of myocardial fatty acid metabolism through various interventions to delineate gender differences in fatty acid metabolism and ROS production and the interplay with myocardial energetics and function. To that end, we will perform in-vivo measurements of myocardial oxygen consumption (using C-acetate) and FA utilization oxidation and esterification (using C-palmitate) with PET; myocardial energetics as defined by the phosphocreatine and adenosine triphosphate concentrations and their ratio and creatine kinase flux using P-MRS; and left ventricular structure/ work by MRI and superoxide levels by optical imaging of DHE oxidation. In addition, relevant gene/protein expression and enzymatic assays will be performed to support the results of the aim. As suggested earlier, the aims converge with PET method being used to measure superoxide production based on results from SA2. The most promising compound will then undergo toxicity studies in preparation for an exploratory new drug (xIND) application necessary for future clinical use. By completing these Aims we well positioned to evaluate in humans a new PET imaging approach capable of measuring tissue superoxide levels. Moreover, we will have gained important mechanistic insights into the nexus between gender and the diabetic cardiomyopathic process and how the relationship between increased FA metabolism and oxidative stress are contributory. As a consequence, we will now be capable of performing similar studies in humans and gaining key pieces of information that should favorably impact the management of the diabetic patient as well as in other diseases where oxidative stress plays an important role.
Oxidative stress due to the production of reactive oxygen species is central to the cause of a variety of diseases such as cancer, neurological disorders, and rheumatological disease. It is particularly important in heart disease secondary to diabetes mellitus, a condition that is more pronounced in women than in men. Currently, we are unable to measure reactive oxygen species noninvasively within an organ such as the heart. In this grant we will develop such a method using positron emission tomography in an animal model of diabetic heart disease. The availability of this method should greatly improve our ability to understand and treat various and favorably impact human health.
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