Cerebrovascular Atherosclerosis: Genes & Gene Expression

描述（由申请人提供）：美国每年发生超过780,000例中风，其中至少125,000例与大血管脑血管粥样硬化直接相关。动脉粥样硬化是一种复杂的遗传性疾病，糖尿病、高脂血症和其他血管危险因素导致内皮损伤导致炎症反应。虽然一般的炎症级联反应已被描述，但动脉粥样硬化中损伤反应机制的具体病理生理介质尚不清楚。在已建立的猪动脉粥样硬化模型中识别动脉粥样硬化相关的基因和途径，有望阐明人类动脉粥样硬化的发病机制，并导致减轻脑血管疾病负担的特异性治疗干预措施。我们的中心假设是，与正常血管相比，在动脉粥样硬化和动脉粥样硬化前的脑血管中，促炎和抗炎介质的编码基因表达差异，有利于促炎蛋白谱。本课题的具体目的是：1)建立一种新的颈动脉和颅内动脉粥样硬化的大型动物模型，即糖尿病/高脂血症猪，同时测试胰岛素治疗对动脉粥样硬化的影响；2)确定脑血管粥样硬化过程中关键介质分子（12脂氧合酶、白细胞介素-1受体拮抗剂和单核细胞趋化蛋白-1）的基因组学、蛋白质组学和功能活性；3)鉴定动脉粥样硬化、动脉粥样硬化前、正常脑血管和脑血管前血管中的差异表达基因。培训目标是拓宽首席研究员在炎症和遗传机制的基础中风研究方面的教育，发展其在动脉粥样硬化基因表达和分子基础方面的专业知识，并促进其研究团队的发展。完成后，我们期望缩小与脑血管粥样硬化和血管危险因素相关的候选炎症基因的范围。这些数据将为未来的病例对照研究提供知情的候选基因选择。总的来说，这些结果将把以前怀疑的和新的炎症介质与动脉粥样硬化和斑块进展联系起来，为治疗这种疾病和预防其破坏性并发症（包括中风）提供潜在的靶点。

DESCRIPTION (provided by applicant): Over 780,000 strokes occur annually in the U.S. with at least 125,000 directly related to large vessel cerebrovascular atherosclerosis. Atherosclerosis is a complex genetic disease in which diabetes, hyperlipidemia and other vascular risk factors result in endothelial injury leading to an inflammatory response. Although the general inflammatory cascade has been described, specific pathophysiological mediators of the response-to-injury mechanisms in atherogenesis are not known. Identification of genes and pathways involved in atherosclerosis in an established porcine model of atherosclerosis is expected to elucidate the pathogenesis of human atheroselerosis and lead to specific therapeutic interventions that reduce the burden of cerebrovascular disease. Our central hypothesis is that genes coding for pro- and counter-inflammatory mediators will be differentially expressed in atherosclerotic and pre-atherosclerotic cerebral vessels compared with normal vessels favoring a pro-inflammatory protein profile. The Specific Aims of this proposal are to 1) Characterize a new large animal model of carotid and intracranial atherosclerosis, the diabetic/hyperlipemic pig simultaneously testing the effect of insulin treatment on atherosclerosis, 2) identify the genomic, proteomic and functional activities of key mediator molecules during the cerebrovascular atherogenesis (12 lipoxygenase, interleukin-1 receptor antagonist and monocyte chemotactic protein-I), and 3) identify differentially expressed genes in atherosclerotic, pre-atherosclerotic, and normal cerebral and precerebral vessels. The training goals are to broaden the principal investigator's education in basic stroke research on inflammatory and genetic mechanisms, to develop his expertise in gene expression and molecular basis of atherosclerosis, and to facilitate his development of a research team. Upon completion, we expect to have narrowed the range of candidate inflammatory genes associated with cerebrovascular atherosclerosis and related to vascular risk factors. This data will allow informed selection of candidate genes for future case-control studies. Collectively, these outcomes will associate previously suspected and novel inflammatory mediators with atherogenesis and plaque progression providing potential targets for treatment of this disease and prevention of its devastating complications, including stroke.