INFLAMMATORY MEDIATORS LEAD TO CAROTID PLAQUE INSTABILITY AND RUPTURE

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。 颈动脉和冠状动脉疾病分别通过动脉粥样硬化斑块破裂导致中风和心肌梗死。本研究旨在探讨颈动脉内膜剥脱术(CEA)患者颈动脉内膜剥脱术(CEA)中不稳定斑块和稳定斑块的生物学特征，为开发新的斑块稳定场所提供科学依据。该项目的长期目标是明确炎症介质在他汀类颈动脉粥样硬化斑块稳定和卒中预防中的重要性，并确定潜在的斑块稳定的新靶点。颈动脉粥样硬化性疾病是美国中风的第三大原因，其发病率占社会成本的550亿美元以上。颈动脉粥样硬化斑块变得不稳定并导致脑或眼部缺血事件的机制尚不清楚。包括The Investigator在内的不同组织已经确定了与脆弱的颈动脉斑块相关的各种炎症介质。这些物质包括抗炎细胞因子和omega-3脂肪酸(请看“初步结果”)。这些数据导致了一种假设，即稳定和不稳定的颈动脉斑块之间存在关键的分子差异。这项翻译研究拨款的具体目的是1)将整个蛋白质组研究与临床相关整合起来，以确定颈动脉斑块不稳定的机制，以及2)测试这些分子是否与他汀类药物治疗的动脉粥样硬化斑块稳定有关。我们的总体目标是确定动脉粥样硬化斑块稳定的潜在新场所。 AIM 1的研究将a)确定与颈动脉斑块易损性有关的新的炎症分子，b)旨在确定稳定斑块的潜在新的治疗靶点。我们将利用强大的实验手段，包括斑块蛋白质组学分析、免疫组织化学和分子生物学技术来研究各种分子在颈动脉斑块不稳定性中的作用。目标2中的研究将检验这样一个假设，即不稳定颈动脉斑块的蛋白质组特征决定了他汀类药物对动脉粥样硬化斑块的稳定性。 我们的目标是更好地了解颈动脉斑块的不稳定性，并为开发新的有效治疗方法做出贡献。这项建议中获得的信息将为合理检查和指导高度颈动脉粥样硬化性疾病患者未来的治疗发展提供一个框架。

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. Carotid and coronary disease lead to stroke and myocardial infarction, respectively, through atherosclerotic plaque rupture. This translational research project aims to investigate in patients with high-grade carotid atherosclerotic disease undergoing carotid endarterectomy (CEA) surgery the biology of unstable and stable plaques and provide the scientific foundation for development of new venues in plaque stabilization. The long-term objective of this project is to define the significance of inflammatory mediators in statin-carotid atherosclerotic plaque stabilization and prevention of stroke and identify potential novel targets for plaque stabilization. Carotid atherosclerotic disease is the third leading cause of stroke in the United States and the morbidity accounts for over $55 billion in societal costs. The mechanism by which a carotid atherosclerotic plaque becomes unstable and causes cerebral or ocular ischemic events is poorly understood. Various groups, including the Investigator, have identified a variety of inflammatory mediators that are associated with vulnerable carotid plaques. These include anti-inflammatory cytokines and omega-3 fatty acids (please see 'Preliminary Results'). These data have led to the hypothesis that there are key molecular differences between stable and unstable carotid plaques. The Specific Aims of this translational research grant are 1) to integrate whole proteome studies with clinical correlates to define the mechanisms of carotid plaque instability and 2) test whether these molecules are associated with statin-drug atherosclerotic plaque stabilization. Our overall aim is to identify potential new venues of atherosclerotic plaque stabilization. Studies in Aim 1 will a) determine novel inflammatory molecules involved in carotid plaque vulnerability and b) aim to identify potentially novel therapeutic targets for plaque stabilization. Powerful experimental approaches, including plaque proteomic analysis, immunohistochemistry, and molecular biology techniques will be used to study the role of various molecules in carotid plaque instability. Studies in Aim 2 will test the hypothesis that the proteomic signature of unstable carotid plaques determines statin-drug atherosclerotic plaque stabilization. We aim for a better understanding of carotid plaque instability and contribute to the development of novel effective therapies. The information obtained in this proposal will provide a framework to rationally examine and direct future therapy development for patients with high-grade carotid atherosclerotic disease.