Effect of Age on Vein Graft Neointimal Formation

年龄对静脉移植新内膜形成的影响

• 批准号: 6684679
• 负责人: BRIAN CROCKETT COOLEY
• 金额: $ 7.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684679
• 关键词: age difference; aging; beta galactosidase; biological models; blood vessel transplantation; genetically modified animals; hyperplasia; laboratory mouse; morphometry; postoperative complications; reporter genes; vascular endothelium

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.

10.干细胞、组织修复和衰老中的细胞替代。 临床上，静脉移植用于缺血的心脏和下肢的血运重建。虽然这些手术取得了急性成功，但估计有20-50%的人在五年内发生狭窄，这是由新生内膜细胞过度增殖引起的。新治疗方向的实验评价仅在年轻动物模型中进行，尽管这些临床程序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了年龄相关差异。拟议的研究将评估静脉移植物新生内膜发展程度随年龄变化的假设。实验设计将利用在年轻和年老动物之间移植移植物的能力，以区分局部组织效应和全身效应（例如，激素）作用。 此外，转基因小鼠品系-Rosa 26小鼠，其在所有细胞中组成型表达β-半乳糖苷酶报告基因-将用于区分新生内膜细胞的移植物与受体细胞来源。将通过组织形态计量学比较新生内膜形成的程度，并通过报告基因对细胞来源进行二次评价。在此基础上，未来的研究将通过基因敲入和基因敲除小鼠， 模型此外，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治疗途径进行年龄特异性评估。