Cell and matrix interactions in diabetic vascular tissue engineering models

糖尿病血管组织工程模型中细胞和基质的相互作用

基本信息

批准号：
9383944
负责人：
Agneta Simionescu
金额：
$ 32万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9383944
关键词：
Advanced Glycosylation End Products Affect American Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Arterial Fatty Streak Arteries Artificial Implants Atherosclerosis Binding Biochemical Biocompatible Materials Bioreactors Blood Glucose Blood Vessels Caliber Cardiovascular system Cells Chemicals Clinical Research Collagen Cytoskeleton Deposition Development Devices Diabetes Mellitus Disease Dyslipidemias Elastin Endothelial Cells Endothelium Environment Event Extracellular Matrix Fibroblasts Fibrosis Future Glucose Goals Growth Heart Valves Human Hypertrophy Impaired wound healing Implant Incubated Inflammation Inflammatory Response Injury Kidney Light Link Literature Mechanics Mesenchymal Metformin Modeling Modification Monitor Morphology Myocardium NADPH Oxidase Nerve Nude Rats Operative Surgical Procedures Oxidative Stress Pathologic Pathology Patients Physiological Problem Solving Process Production Proliferating Proteins Rattus Reactive Oxygen Species Resistance Risk Factors Role Smooth Muscle Myocytes Stimulus TLR4 gene Testing Tissue Engineering Tissues Tunica Adventitia Vascular Diseases Vascular remodeling abdominal aorta base blood lipid calcification cardiovascular risk factor cell type crosslink diabetic diabetic patient emergency service responder expectation high risk human tissue immunoregulation implantation injured insulin sensitizing drugs monocyte non-diabetic oxidation receptor repaired response scaffold three-dimensional modeling tissue support frame vasa vasorum vascular tissue engineering

项目摘要

Diabetes is a major risk factor for vascular diseases that affects nearly all blood vessel types and calibers. In diabetes, elevated levels of blood glucose and lipids interact irreversibly with long-lived proteins, such as collagen and elastin from the blood vessel wall, via oxidation and crosslinking processes, resulting in formation of advanced glycation end products (AGEs); the consequence is vascular stiffening, the hallmark of diabetes. Furthermore, vascular cells respond to diabetes- related altered environment by activation and leading to pathological remodeling and to the onset and progression of vascular disease. Together, these severe cell and extracellular matrix (ECM) changes result in activation of inflammation, impaired healing, fibrosis, and ectopic calcification. The interaction of AGEs with their receptor, RAGE, stimulates the production of reactive oxygen species, leading to dysfunctional remodeling of the vascular wall (stiffening, fibrosis, and calcification). The goal of this project is to characterize the effect of diabetes on the adventitial fibroblasts and their involvement in vascular pathology. By using 3D models based on tissue engineering principles, we can control the type of cells seeded on a vascular matrix-based scaffold while providing the necessary biochemical and mechanical stimuli in a physiologic bioreactor. The tissue engineered construct can also be implanted in diabetic animal models, to explore the effect of ECM oxidation and AGE accumulation on the fate of adventitial fibroblasts. The effect of antioxidant and anti-inflammatory agents can also be monitored. Our hypothesis is that fibroblasts are activated by ROS and contribute to the dysfunctional remodeling of the vascular wall in response to diabetes-induced injuries. This hypothesis will be tested in the following two aims. In specific Aim 1 we will investigate the contribution of diabetic adventitial fibroblasts to the pathological vascular wall remodeling. Vascular ECM-based scaffolds (acellular arteries) will be seeded with human endothelial cells, smooth muscle cells, and fibroblasts and a) incubated in a physiologic vascular bioreactor for 2 months in diabetic media, b) implanted as transposition grafts in the abdominal aorta of normal and diabetic nude rats for 3 and 6 months. Grafts will be monitored for oxidative stress and inflammation. In specific Aim 2 we will explore the fate of diabetic adventitial fibroblasts in the presence of antioxidant and anti-inflammatory agents. Vascular ECM-based scaffolds seeded with human vascular cells will be a) incubated in a physiologic vascular bioreactor for 2 months in diabetic media and b) implanted as transposition grafts in the abdominal aorta of normal and diabetic nude rats for 3 and 6 months, in the presence of antioxidant polyphenolic compounds, metformin, an insulin- sensitizer drug, and immunomodulatory mesenchymal cells (in separate groups). Grafts will be monitored for oxidative stress and inflammation. Expectations: at the conclusion of this study, we would gain important information about the major diabetes-related alterations in the vascular wall initiated by the adventitial fibroblasts, potentially offering avenues for targeting these events.

糖尿病是血管疾病的主要危险因素，几乎影响所有血管类型和口径。在糖尿病中，血糖和脂质的水平升高与长寿相互作用蛋白质，例如血管壁上的胶原蛋白和弹性蛋白，通过氧化和交联过程，导致高级糖基化终产物的形成（年龄）；结果是血管僵硬，糖尿病的标志。此外，血管细胞对糖尿病反应相关环境通过激活和导致病理重塑以及发作和发作和血管疾病的进展。这些严重的细胞和细胞外基质（ECM）也会改变导致激活炎症，愈合受损，纤维化和异位钙化。年龄与其受体的相互作用，愤怒，刺激活性氧的产生物种，导致血管壁的重塑功能障碍（僵硬，纤维化和钙化）。该项目的目的是表征糖尿病对外膜成纤维细胞及其的影响参与血管病理学。通过使用基于组织工程原理的3D模型，我们可以控制基于血管基质的支架上的细胞类型，同时提供必要的生理生物反应器中的生化和机械刺激。组织工程结构可以也将其植入糖尿病动物模型中，以探索ECM氧化和年龄的影响累积在外膜成纤维细胞的命运上。抗氧化剂和抗炎的作用也可以监视代理。我们的假设是成纤维细胞被ROS激活并导致功能障碍响应糖尿病引起的损伤的血管壁重塑。这个假设将是在以下两个目标中进行了测试。在特定目的1中，我们将研究糖尿病性外膜成纤维细胞对病理血管壁重塑。基于血管ECM的支架（细胞动脉）将是用人内皮细胞，平滑肌细胞和成纤维细胞播种，a）在A中孵育生理血管生物反应器在糖尿病培养基中持续2个月，b）植入作为转置移植物正常和糖尿病裸鼠的腹主动脉3和6个月。将监视移植物氧化应激和炎症。在特定目的2中，我们将在存在的情况下探索糖尿病性外膜成纤维细胞的命运抗氧化剂和抗炎药。基于ECM的血管基于人类的脚手架血管细胞将在糖尿病培养基中在生理血管生物反应器中孵育2个月 b）在正常和糖尿病裸鼠的腹主动脉中植入作为换位移植物，为3 和6个月，在存在抗氧化剂多酚化合物的情况下，二甲双胍，一种胰岛素敏化剂药物和免疫调节性间充质细胞（分别分别）。移植物将是监测氧化应激和炎症。期望：在本研究结束时，我们将获得有关主要的重要信息外膜成纤维细胞引发的血管壁中与糖尿病相关的改变，可能提供针对这些事件的途径。