Cardiovascular disease is the major cause of mortality in developed countries claiming 870,000 deaths/year in US alone (year 2004 statistics). With cases on the rise in the developing countries as well the associated raising costs in managing the afflicted population will have global implications and urgently require paradigm-shifting approaches to diagnosis and monitoring of disease progression. In this proposal we suggest to develop and apply novel molecular imaging probes for detecting the changes in the repertoire of cell-generated mediators typical of local inflammation in the vascular wall as the early signal of cardiovascular disease progression. Myeloperoxidase (MPO, one of the components released by PMNs via triggered exocytosis) is a unique catalytically active marker of inflammation sites, implicated in progression of vascular pathologies, e.g. unstable atheroma. We previously developed and applied MR signal amplification strategy for imaging of MPO enzymatic activity using paramagnetic bisamides of GdDTPA as reducing substrates of MPO. Due to the fact that MPO binds to the cell surface and is retained at the site of inflammation, the potential applications of MPO imaging are numerous and range from stroke imaging to imaging of vascular wall pathologies. Building on our previous research applying MR and nuclear imaging to visualization of culprits of inflammation of the vascular wall we propose to perform optimization of MPO molecular imaging probe with the focus on probe stability and potential translation of our research. We also propose to design novel dual-function sensors for MPO imaging. MPO activity in vascular lesions is rate-limited by the rates of local hydrogen peroxide production. Hydrogen peroxide is a product of superoxide/hydrogen peroxide pathway activation in many cells populating blood vessel wall (PMN, monocytes and endothelial cells), which respond by activating intracellular NADPH oxidase. We propose to synthesize and test in model systems paramagnetic superoxide dismutase (SOD) mimic-MPO substrates based on chelated paramagnetic Mn(II) and Gd(III), which supply additional hydrogen peroxide, and simultaneously report on MPO activity due to the ability to bind to proteins of cell surface and extracellular matrix. We propose optimization steps, feasibility testing using radioisotope methods and toxicity testing before in vivo imaging. The proposal will pursue three major aims: 1) develop novel synthetic approaches and building blocks for optimizing myeloperoxidase reporter probes (MPO-specific paramagnetic chelates);2) characterize the developed molecular imaging probes: enzyme reporting, dismutase mimic properties and stability in vitro;3) perform testing of molecular probes for imaging oxidative response in vivo.
Diseased blood vessel walls frequently develop lesions that can become unstable and rupture. The rupture leads to blocking blood supply and death of tissues in the brain and heart and may result in debilitating disease and loss of life. We propose to develop agents that can report on areas of instability in blood vessels and detoxify some of the reactive molecules that cause instability, which has implications in preventing heart attacks and strokes by identifying patients who carry unstable lesions and who can benefit from early treatment of such unstable lesions.
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