|
In this grant proposal to TRDRP, my research group plans to develop a family of vastly sensitive and rapid in vivo imaging techniques by which tobacco-users can be screened for their stroke and heart attack risks, and to initiate and monitor the efficacy of preventative, therapeutic interventions. Epidemics of tobacco use coincide with epidemics of cerebrovascular disease, particularly stroke, contributing to a serious increase in the burden of preventable disease and to the spiraling health-care costs. In many studies, most notably a recent published survey in the New England Journal of Medicine, it is clear that the relationship is not mere coincidence, but that tobacco use by smokers significantly increases their incidence of stroke. A second well researched relationship concerns the causative nature of atherosclerosis accumulation of lipid as plaque in the walls of major blood vessels of both the brain and heart, and the increased incidence of stroke and heart attack. Both of these common, life threatening diseases result from occlusion of smaller blood vessels by pieces of the atheroma plaque which break free and are carried to the distant site where they are large enough to block the major supply of blood, oxygen and nutrients to the brain and heart, respectively. The latter scenario, that atheroma plaque has structure, which in turn may determine whether the patient suffers such an adverse event, or continues without obvious symptoms. This is the hypothesis of "vulnerable-plaque". In a recent study, pathologists confirmed that smokers showed higher incidence of "vulnerable plaque" than the more stable atheroma plaque. The stage is therefore well set for the study proposed in this grant submission. Urgently needed is an inexpensive, yet specific and sensitive screening examination, for the earliest detection of vulnerable plaque in both the carotid artery and if possible, in the coronary arteries. The single greatest impediment to the use of conventional imaging techniques is its very limited sensitivity. The goal of this proposal is thus to address this issue by developing a family of ultrasensitive and ultrafast MRI and MRS techniques capable of detecting and characterizing plaques in animal models in a timely and cost effective way. Our proposal brings dramatic signal enhancements of over 50,000 fold to conventional MRI and MRS by utilizing two techniques of hyperpolarization: PASADENA (Parahydrogen And Synthesis Allows Dramatically Enhanced Nuclear Alignment) & DNP (Dynamic Nuclear Polarization). Furthermore, our proposal advances the field by identifying a family of potential biomarkers which, when localized by the MR strategies available, will undoubtedly improve our ability to image plaque in vivo. Finally, given the complexity of plaque chemistry, with a mixed cellular composition, and lipid content, the whole issue of "vulnerability" will be defined much more carefully by our novel in vivo methods. Together, PASADENA and DNP will provide a selection of agents designed to characterize atheroma plaque at a chemical and functional level. A detailed analysis of novel imaging and current histopathological information should result in new screening tools for smokers. This return to the original hypothesis: early detection and definition of vulnerable plaque will, as a result of early medical interventions, improve life expectancy of smokers and reduce health care costs for the society. |
