Diabetes Resistant Vascular Graft Remodeling

项目摘要 糖尿病是心血管疾病的主要危险因素，血管僵硬和钙化是 被认为是糖尿病的标志。因此，工程血管移植物的主要需求是长时间的- 用于糖尿病心血管患者的术语通畅性和耐久性。基于组织工程的构建物 胶原蛋白和弹性蛋白支架和自体祖细胞在治疗血管疾病方面有着巨大的希望， 但关于他们在糖尿病环境中的命运的信息很少。血糖和血脂的变化 糖尿病的代谢特点导致内皮功能障碍、动脉粥样硬化加速、活化 炎症、纤维化和愈合受损，所有这些都不利于理想的整合和 组织工程化结构的重塑。 这项研究的长期目标是开发可行的组织工程化血管替代品，以适应 耐受糖尿病相关并发症。初步数据有力支持的假设是 基质和细胞都会在糖尿病环境中受到影响，以胶原蛋白和弹性蛋白为基础的治疗 含有多酚的支架将保护基质免受僵硬和钙化。为了检验这些假设， 脂肪干细胞种植的血管支架将作为直接端到端植入2型糖尿病大鼠体内。 腹主动脉末端吻合，以及它们的重塑和存活率将被研究(目标1)。至 为了减轻糖尿病引起的改变，支架将在进行多酚稳定剂处理之前 细胞接种，移植物将被植入糖尿病大鼠体内(目标2)。国际和平组织的科学家导师Dr。 Vyavahare、该Cobre的PI和临床导师兰根博士与该项目密切相关；核心支持 对于干细胞的分离和鉴定以及动物血管支架的生物成像是必不可少的。 成功的项目。 通常，组织工程化结构及其重塑在健康动物身上进行临床前测试 评估。使用糖尿病动物模型将提供关于这一分子机制的新信息。 糖尿病环境中胶原和弹性蛋白支架的病理和命运。组织的治疗- 含有多酚的衍生血管支架最终将保护它们免受糖尿病并发症和 支持它们未来在糖尿病患者心血管组织工程中的应用。

Project Summary Diabetes is a major risk factor for cardiovascular diseases, and vascular stiffening and calcification are considered the hallmark of diabetes. Therefore there is a major need for engineered vascular grafts with long- term patency and durability to be used in diabetic cardiovascular patients. Tissue-engineered constructs based on collagen and elastin scaffolds and autologous progenitor cells hold great promise to treat vascular diseases, but very little information exists regarding their fate in the diabetic environment. The altered glucose and lipid metabolism characteristic of diabetes results in endothelial dysfunction, accelerated atherosclerosis, activation of inflammation, and fibrosis and impaired healing, all of which are not conducive to the desired integration and remodeling of tissue engineered constructs. The long-term goal of this research is to develop viable tissue-engineered vascular substitutes adapted to withstand diabetes-related complications. The hypotheses, robustly supported by preliminary data, are that both matrix and cells are affected in a diabetic milieu and that treatment of collagen- and elastin-based scaffolds with polyphenols would protect the matrix from stiffening and calcification. To test these hypotheses, adipose derived stem cell-seeded vascular scaffolds will be implanted in type 2 diabetic rats as direct end-to- end anastomoses in the abdominal aorta, and their remodeling and survival will be investigated (Aim 1). To mitigate diabetes-induced alterations, the scaffolds will be treated with polyphenol stabilizing agents prior to cell seeding, and the grafts will be implanted in diabetic rats (Aim 2). Expertise of the PI's scientist mentor, Dr. Vyavahare, PI of this COBRE, and clinical mentor, Dr. Langan, are greatly relevant to the project; core support for stem-cell isolation and characterization and bioimaging of vascular scaffold in animals is essential for this project to succeed. Typically, tissue-engineered constructs and their remodeling are tested in healthy animals for preclinical evaluation. Using a diabetic animal model will provide new information about the molecular mechanisms of this pathology and the fate of collagen- and elastin-based scaffolds in a diabetic environment. Treatment of tissue- derived vascular scaffolds with polyphenols will eventually protect them from diabetic complications and support their future use for cardiovascular tissue engineering in diabetic patients.