Effect of Age on Vein Graft Neointimal Formation

10.衰老中的干细胞、组织修复和细胞替换。 临床静脉移植用于缺血心脏和肢体的血运重建。尽管这些手术获得了急诊的成功，但估计有20%-50%的患者在五年内经历了狭窄，这是由于新生内膜细胞的过度增殖引起的。尽管这些临床操作在老年患者中普遍存在，尽管在动脉损伤诱导的新生内膜形成模型中发现与年龄相关的差异，但新治疗方向的实验评估仅在年轻动物模型中进行。这项拟议的研究将评估静脉移植物新生内膜发育程度随年龄变化的假设。实验设计将利用幼年和老年动物之间移植移植物的能力，区分局部组织效应和全身(例如，荷尔蒙)效应。 此外，一种在所有细胞中结构性表达β-半乳糖苷酶报告基因的转基因小鼠系--rosa26小鼠--将用于区分新生内膜细胞的移植物和受体细胞来源。新生内膜形成的程度将通过组织形态计量学进行比较，并通过报告基因对细胞来源进行二次评估。基于这项工作的未来研究将通过使用敲入和敲除小鼠来调查与年龄相关的新生内膜增殖差异的遗传基础。 模特们。此外，建立与年龄相关的静脉移植模型将允许对抑制新生内膜形成的新的治疗途径进行特定年龄的评估。

10. Stem Cells, Tissue Repair, and Cell Replacement in Aging. Clinical vein grafting is used to revascularize ischemic hearts and lower limbs. Although acute success is achieved in these procedures, an estimated 20-50% undergo stenosis within five years, caused by a hyperproliferation of neointimal cells. Experimental evaluation of new therapeutic directions has been conducted in exclusively young animal models, despite the prevalence of these clinical procedures in older patients and despite findings of age-associated differences in arterial injury-induced models of neointimal formation. The proposed study will evaluate the hypothesis that the extent of vein graft neointimal development varies with age. The experimental design will take advantage of the capacity for transplanting grafts between young and old animals, to discern local tissue effects from systemic (e.g., hormonal) effects. Furthermore, a transgenic mouse line -- Rosa26 mice, which constitutively express the beta-galactosidase reporter gene in all cells -- will be used to discriminate graft versus recipient cell sources of neointimal cells. The extent of neointimal formation will be compared histomorphometrically, with secondary evaluation of cell source through the reporter gene. Future studies based on this work will investigate the genetic basis of age-associated differences in neointimal proliferation through the use of knock-in and knock-out mouse models. Furthermore, the establishment of an age-associated model of vein grafting will permit age-specific evaluation of new therapeutic avenues for inhibiting neointimal formation.