REACTIVE CARBONYL SPECIES AND CEREBRAL MICROVASCULAR DISEASES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Individuals with diabetes mellitus (DM) have cerebral microvascular diseases including ischemic and lacunar strokes at rates three to five times higher than that of the general population. The extent of brain damage following a stroke is also aggravated in these individuals. Even more troubling, are the observations that diabetic patients who have tight blood glucose control still develop cognitive impairment and are at a higher risk of developing spontaneous Alzheimer's disease. Recent studies suggest that these defects stem in part from an increase in blood-brain-barrier (BBB) permeability. What remain elusive are the molecular triggers responsible for initiating BBB breach. Exciting new data emerging from our laboratory as well as a few others indicate that reactive carbonyl species (RCS) generated during diabetes may be one of these triggers. Our working hypothesis is that "RCS generated during diabetes interact with and compromise the function of endothelial cells resulting in BBB breach and increased incidence of Neurological disorders." We will use in vitro studies to elucidate mechanisms by which RCS compromise brain endothelial cell function and in vivo studies to show that chronic elevation of RCS leads to blood brain barrier breach and an increase in cerebral damage following cerebral artery occlusion. The proposed research will provide data in support of the concept of "RCS-ROC coupling." It will also provide mechanistic insights into how this group of understudied cellular oxidants impairs endothelial cell function leading to incrased BBB permeability, the basis for a direction of an R01 application. More globally, data from the proposed research could also be useful for developing newer therapeutic strategies to slow the progression of cardiovascular diseases during diabetes, improve the quality of life of diabetic patients and control the escalating economic cost of diabetes care, which is estimated to be in excess of $132 billion annually.