REACTIVE CARBONYL SPECIES AND CEREBRAL MICROVASCULAR DISEASES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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。中风后大脑损伤的程度在这些人中也会加剧。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与内皮细胞功能相互作用，并损害内皮细胞的功能，导致血脑屏障破坏，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，拟议研究的数据还可能有助于开发新的治疗策略，以减缓糖尿病期间心血管疾病的进展，改善糖尿病患者的生活质量，并控制糖尿病护理不断攀升的经济成本，据估计，每年的经济成本超过1320亿美元。

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.