SELECTINS ROLE IN VASCULAR INJURY IN GENE-TARGETED MICE

描述：经皮介入治疗后的呼吸仍然是一个主要的 挑战，发生在20- 40%后，球囊血管成形术或支架。 新生内膜形成是一个重要的机制，代表了一个复杂的愈合 这一过程包括炎性细胞和炎症细胞之间的粘附相互作用。 血管壁选择素粘附分子参与了 白细胞募集，但它们在血管损伤后的确切作用是 不完全理解。因此，本提案的主要目标是 了解E-和P-选择素的作用及其在中性粒细胞上的相互作用 和巨噬细胞/泡沫细胞积聚和动脉后新生内膜生长 使用apoE + P-选择素表达缺陷基因靶向小鼠的损伤 和/或E-选择素的单克隆抗体和针对E-和/或E-选择素的单克隆抗体， P-选择素SpecificAim 1将检验消除 通过基因靶向的P-选择素和/或E-选择素限制白细胞进入， 颈动脉剥脱损伤后血管内膜增生 apoE缺陷小鼠。组织形态计量学和详细的免疫组织化学分析 将与系列MRI成像一起使用。虽然P-选择素 最近被证明在调节白细胞方面具有突出的作用 行为在小鼠模型的炎症，都离散功能差异 并且描述了E-和P-选择素的类似/重叠功能。 因此，具体目标2将检验瞬时抑制 E-选择素、P-选择素或两者的结合， 一起限制白细胞进入和积聚以及新生内膜形成 在基因靶向小鼠颈动脉剥脱损伤后， apoE的表达。为了解决P-选择素被抑制的具体机制， 有望发挥其对导丝术后血管修复的保护作用 剥脱性损伤，将在目标3中进行骨髓移植。 具体目标3将检验血小板P-选择素是负责 P-选择素缺失/阻断对白细胞的保护作用 颈动脉剥脱损伤后血管内膜增生 基因靶向小鼠apoE表达缺陷。综上所述各项 研究将提供新的见解选择素的作用， 血管损伤后炎性细胞运输和新生内膜生长 动脉粥样硬化倾向apoE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.