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，血管硬化和钙化是 糖尿病的标志因此，主要需要具有长- 长期通畅性和耐久性，用于糖尿病心血管患者。基于组织工程的结构 胶原蛋白和弹性蛋白支架和自体祖细胞上的细胞对治疗血管疾病有很大的希望， 但是关于它们在糖尿病环境中的命运的信息非常少。血糖和血脂的改变 糖尿病的代谢特征导致内皮功能障碍，加速动脉粥样硬化，活化 炎症、纤维化和愈合受损，所有这些都不利于所需的整合， 组织工程构建物的重塑。 这项研究的长期目标是开发可行的组织工程血管替代物， 承受糖尿病相关的并发症。初步数据有力支持的假设是， 基质和细胞在糖尿病环境中都受到影响， 具有多酚的支架将保护基质免于硬化和钙化。为了检验这些假设， 将脂肪来源的干细胞接种的血管支架植入2型糖尿病大鼠中，作为直接的末端- 将研究腹主动脉中的终末动脉瘤，以及它们的重塑和存活（目的1）。到 为了减轻糖尿病诱导的改变，支架将在施用前用多酚稳定剂处理。 细胞接种，并将移植物植入糖尿病大鼠中（目的2）。PI的科学家导师Dr. COBRE的PI Vyavahare和临床导师Langan博士与该项目密切相关;核心支持 干细胞的分离和表征以及动物血管支架的生物成像对此至关重要 项目成功。 通常，在健康动物中测试组织工程化构建体及其重塑，用于临床前研究。 评价使用糖尿病动物模型将提供关于这种分子机制的新信息。 糖尿病环境中胶原蛋白和弹性蛋白基支架的病理学和命运。组织处理- 含有多酚的衍生血管支架将最终保护它们免受糖尿病并发症的影响， 支持其未来用于糖尿病患者的心血管组织工程。

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.