SELECTINS ROLE IN VASCULAR INJURY IN GENE-TARGETED MICE

描述：经皮介入治疗后的再狭窄仍然是主要的 挑战，发生在球囊血管成形术或支架术后的20%-40%。 新生内膜的形成是一种重要的机制，代表着复杂的愈合过程 包括炎症细胞和血管内皮细胞之间的黏附相互作用的过程 血管壁。选择素黏附分子参与血管生成的早期步骤 白细胞招募，但它们在血管损伤后的确切作用是 不完全理解。因此，这项提案的主要目标是 了解E-和P-选择素在中性粒细胞中的作用及其相互作用 动脉后巨噬细胞/泡沫细胞积聚和新生内膜生长 载脂蛋白E和P-选择素表达缺失的基因靶向小鼠的损伤 和/或E-选择素和针对E-和/或的单抗 P-选择素。SpecificAim1将测试以下假设 P-选择素和/或E-选择素通过基因靶向限制白细胞进入和 大鼠颈动脉剥脱伤后血管内膜积聚和新生内膜形成 APOE缺陷小鼠。组织形态计量学和详细的免疫组织化学分析 将与序列磁共振成像一起使用。尽管P-选择素有 最近被证明在调节白细胞方面扮演着重要的角色 在小鼠炎症模型中的行为，两者功能上的离散差异 并且描述了E-和P-选择素的相似/重叠功能。 因此，《特定目标2》将检验暂时性抑制的假设 E-选择素、P-选择素或两者均使用封闭的单抗 共同限制白细胞进入和积聚以及新生内膜的形成 基因靶向基因缺陷小鼠颈动脉剥脱损伤 载脂蛋白E的表达。探讨P-选择素的具体作用机制(S) 有望在钢丝术后血管修复中发挥保护作用 剥脱损伤后，将在AIM 3中进行骨髓移植。 特殊目标3将检验血小板P-选择素负责的假设 P-选择素缺失/阻断对白细胞的保护作用 大鼠颈动脉剥脱伤后血管内膜积聚和新生内膜形成 载脂蛋白E表达缺失的基因靶向小鼠。这些加在一起， 研究将为研究选择素在体内的作用(S)提供新的见解 大鼠血管损伤后炎性细胞迁移与新生内膜生长 易患动脉粥样硬化的载脂蛋白E缺陷小鼠。此外，这些研究将开放 限制新生内膜生长的潜在治疗策略的新途径 血管损伤后。

DESCRIPTION: Restenosis after percutaneous interventions remain a major challenge, occurring in 20-40 percent after balloon angioplasty or stents. Neointima formation is an important mechanism and represents a complex healing process that includes adhesive interactions between inflammatory cells and the vessel wall. The selectin adhesion molecules participate in the early steps of leukocyte recruitment but their exact role after vascular injury is incompletely understood. Accordingly, the primary goal of this proposal is to understand the role of E- and P-selectin and their interactions on neutrophil and macrophage/foam cell accumulation and neointimal growth following arterial injury using gene-targeted mice deficient in expression of apoE plus P-selectin and/or E-selectin and monoclonal antibodies directed against E- and/or P-selectin. SpecificAim1 will test the hypothesis that elimination of P-selectin and/or E-selectin by gene-targeting limits leukocyte entry and accumulation and neointima formation following carotid denudation injury in apoE deficient mice. Histomorphometry and detailed immunohistochemical analysis will be utilized together with serial MRI imaging. Although P-selectin has recently been shown to occupy a preeminent role in regulating leukocyte behavior in a mouse model of inflammation, both discrete functional differences and similar/overlapping functions are described for E- and Pselectin. Accordingly, Specific Aim 2 will test the hypothesis that transient inhibition of E-selectin, P-selectin or both using blocking monoclonal antibodies each or together limit leukocyte entry and accumulation and neointima formation following carotid denudation injury in gene-targeted mice deficient in expression of apoE. To address the specific mechanism(s) by which P-selectin is anticipated to exert its protective effect on vascular repair after wire denudation injury, bone marrow transplantation will be performed in aim 3. Specific Aim 3 will test the hypothesis that platelet P-selectin is responsible for the protective effect of P-selectin deletion/blockade on leukocyte accumulation and neointima formation following carotid denudation injury in gene-targeted mice deficient in expression of apoE. Taken together, these studies will provide new insights into the role(s) of the selectins in inflammatory cell trafficking and neointimal growth after vascular injury in atherosclerosis-prone apoE-deficient mice. In addition, these studies will open new avenues to potential therapeutic strategies to limit neointimal growth after vascular injury.