权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9767842
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/9767842
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 expectation first responder 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.

糖尿病是影响几乎所有血管类型的血管疾病的主要危险因素