Diabetes Resistant Vascular Graft Remodeling

抗糖尿病血管移植重塑

• 批准号: 8742738
• 负责人: Agneta Simionescu
• 金额: $ 19.69万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8742738
• 关键词: Abattoirs; Adipose tissue; Adult; Advanced Glycosylation End Products; Affect; Anastomosis - action; Animal Model; Animals; Antioxidants; Arterial Medias; Atherosclerosis; Autologous; Binding; Biochemical; Biomedical Engineering; Bioreactors; Blood Glucose; Blood Vessels; Caliber; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Separation; Cells; Centers of Research Excellence; Characteristics; Clinical; Collagen; Complex; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Elastin; Engineering; Environment; Extracellular Matrix; Family suidae; Fibrosis; Funding; Future; Glucose; Goals; Impaired wound healing; Implant; In Vitro; Inflammation; Life; Mechanics; Medial; Mentors; Modeling; Molecular; Monitor; Natural regeneration; One-Step dentin bonding system; Pathology; Patients; Pentas; Performance; Peripheral; Peripheral arterial disease; Process; Property; Proteins; Publishing; Research; Resistance; Risk Factors; Scientist; Stabilizing Agents; Stem cells; Stimulus; Streptozocin; Testing; Tissue Engineering; Tissues; Translations; Tunica Adventitia; Vascular Diseases; Vascular Graft; abdominal aorta; base; bioimaging; calcification; crosslink; diabetic; diabetic patient; diabetic rat; endothelial dysfunction; expectation; glucose metabolism; implantation; internal thoracic artery; lipid metabolism; novel; polyphenol; preclinical evaluation; protective effect; scaffold; type I diabetic; vascular tissue engineering; vessel regression

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.

项目概要 糖尿病是心血管疾病的主要危险因素，血管硬化和钙化是心血管疾病的主要危险因素。 被认为是糖尿病的标志。因此，非常需要具有长寿命的工程血管移植物。 用于糖尿病心血管患者的长期通畅性和耐用性。基于组织工程的构建体 胶原蛋白和弹性蛋白支架以及自体祖细胞在治疗血管疾病方面具有巨大的前景， 但关于它们在糖尿病环境中的命运的信息却很少。改变的葡萄糖和脂质 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和 组织工程结构的重塑。 这项研究的长期目标是开发可行的组织工程血管替代品，适应 抵御糖尿病相关并发症。得到初步数据有力支持的假设是： 在糖尿病环境中，基质和细胞都会受到影响，并且基于胶原蛋白和弹性蛋白的治疗 含有多酚的支架可以保护基质免于硬化和钙化。为了检验这些假设， 脂肪干细胞接种的血管支架将被植入 2 型糖尿病大鼠体内，作为直接的端对端 腹主动脉末端吻合术，并将研究其重塑和存活（目标 1）。到 为了减轻糖尿病引起的改变，支架将在使用之前用多酚稳定剂进行处理 细胞接种，并将移植物植入糖尿病大鼠体内（目标 2）。 PI 科学家导师 Dr. 的专业知识 COBRE 的 PI Vyavahare 和临床导师 Langan 博士与该项目密切相关；核心支撑 动物血管支架的干细胞分离和表征以及生物成像对此至关重要 项目取得成功。 通常，组织工程构建体及其重塑在健康动物中进行临床前测试 评估。使用糖尿病动物模型将提供有关其分子机制的新信息 糖尿病环境中基于胶原蛋白和弹性蛋白的支架的病理学和命运。组织处理- 含有多酚的衍生血管支架最终将保护他们免受糖尿病并发症的影响 支持它们未来在糖尿病患者心血管组织工程中的应用。