REACTIVE CARBONYL SPECIES AND CEREBRAL MICROVASCULAR DISEASES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 糖尿病(DM)患者的脑微血管疾病，包括缺血性中风和腔隙性中风，其发病率比普通人群高三到五倍。在这些人中，脑梗塞后的脑损伤程度也会加重。更令人不安的是，有观察到，血糖控制严格的糖尿病患者仍会出现认知障碍，并有更高的风险患上自发性阿尔茨海默病。最近的研究表明，这些缺陷部分源于血脑屏障(BBB)通透性的增加。仍然难以捉摸的是引发血脑屏障破坏的分子触发因素。来自我们实验室的令人兴奋的新数据以及其他一些数据表明，糖尿病期间产生的活性羰基物种(RCS)可能是这些触发因素之一。我们的工作假设是“糖尿病期间产生的RCS与血管内皮细胞功能相互作用并损害其功能，导致血管通透性，增加神经疾病的发生率。”我们将利用体外研究来阐明RCS损害脑内皮细胞功能的机制，并在体内研究表明RCS的慢性升高导致脑动脉闭塞后血脑屏障的破坏和脑损伤的增加。这项拟议的研究将提供支持“RCS-ROC耦合”概念的数据。它还将提供关于这组未被研究的细胞氧化剂如何损害内皮细胞功能导致血脑屏障通透性增加的机械性见解，这是R01应用方向的基础。从全球范围来看，来自拟议研究的数据也可能有助于开发新的治疗策略来减缓病情进展 预防糖尿病期间的心血管疾病，提高糖尿病患者的生活质量，控制 糖尿病护理的经济成本不断上升，估计每年超过1320亿美元。 该项目的具体目标是： 1.阐明甲基乙二醛(MGO)增加脑血管内皮细胞(BEC)氧自由基和功能障碍的机制。 2.观察MGO慢性升高对在体血管内皮细胞功能和血脑屏障通透性的影响，探讨MCAO对大鼠脑损伤的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 an infarct 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 vascular permeability, increasing the 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 increased 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. The specific aims of the project are: 1. To elucidate mechanisms by which methylglyoxal (MGO) increases in reactive oxygen species and dysfunction of brain endothelial cells (BEC). 2. To characterize the effects of chronic elevation of circulating levels of MGO on endothelial cell function and BBB permeability in vivo, and to determine the extent of brain damage following mid cerebral artery occlusion (MCAO) in MGO-treated rats.