Cell-free vascular grafts: immunological response and vascular regeneration

无细胞血管移植物：免疫反应和血管再生

基本信息

批准号：
9912445
负责人：
Stelios Theoharis Andreadis
金额：
$ 57.33万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-10 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912445
关键词：
Address Affect Agonist Anatomy Animal Model Anti-Inflammatory Agents Architecture Arteries Autologous Blood Blood Circulation Blood Vessels Bypass Cardiovascular Diseases Cardiovascular Physiology Carotid Arteries Cause of Death Cells Clinical Clinical Trials Contracts Coronary Arteriosclerosis Development Disease Elderly Endothelium Engineering Environment Exhibits Funding Health Care Costs Heparin Human Immobilization Immune response Implant In Situ In Vitro Infiltration Inflammation Inflammatory Response KDR gene Laboratories Lead Medial Mediating MicroRNAs Modeling Molecular Monitor Mus Natural regeneration Organ Transplantation Pathway interactions Physiological Play Prevalence Productivity Protein Tyrosine Kinase Publications Receptor Signaling Regenerative Medicine Reporting Research Research Personnel Role Sheep Signal Transduction Small Intestinal Submucosa Smooth Muscle Myocytes Surface System Testing Tissue Engineering Transgenic Mice Tyrosine Kinase Domain United States VEGF165 Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vascular Graft Work aging population base cell regeneration clinical application clinically relevant cost endothelial regeneration high throughput technology immunoengineering implantation in vivo in vivo regeneration innovation macrophage monocyte mouse model novel pre-clinical regenerative response scaffold thrombogenesis tissue regeneration transcription factor translational study

项目摘要

ABSTRACT Cardiovascular disease is the leading cause of death in the United States. In particular, coronary artery disease is the most common disorder, with over 350,000 bypass grafting procedures performed every year and an estimated total cost of $26 billion annually, according to the AHA. Tissue engineering approaches using native or synthetic scaffolds and even scaffold-free strategies have developed functional and implantable vascular grafts that have been tested in small and large animal models, as well as in human clinical trials 1-12. In recent years, the field has focused on engineering acellular (A)-TEVs as a potential alternative approach that may provide off-the-shelf grafts for treatment of cardiovascular disease. Recently, we reported successful development of A-TEV based on small intestinal submucosa (SIS) that was functionalized sequentially with heparin and vascular endothelial growth factor (VEGF-165, denoted as VEGF) 13,14. This A-TEV was implanted successfully into the arterial circulation of small (mice) 15 and large (sheep) animal models 13, demonstrating patency, endothelialization and regeneration of contractile vascular wall. Interestingly, VEGF-decorated grafts were populated by anti-inflammatory, M2 macrophages, while vascular grafts containing heparin alone contained mostly M1 type macrophages 15. What is more, VEGF containing grafts had an architecture that was similar to native arteries, in contract to grafts without VEGF (heparin alone), which appeared disorganized and lacked well- defined endothelium and vascular wall. This prompted us to hypothesize that successful regeneration of A-TEV in vivo may depend on generating an anti-inflammatory and pro-regenerative environment, which may be modulated (at least in part) by the immobilized VEGF (iVEGF) decorating the surface of the grafts. In this proposal, we seek to investigate this hypothesis in three specific aims. In Aim 1, we will explore the mechanism through which VEGF modulates the inflammatory response. In Aim 2, we will employ novel transgenic mouse models to monitor monocyte infiltration into the grafts and study the role of VEGF signaling on inflammation and graft regeneration. Finally, in Aim 3 we will explore the long-term patency and remodeling of A-TEV in a large, pre-clinical animal model (ovine) to assess the clinical potential of these grafts. This is a highly innovative proposal that seeks to investigate how regulating the inflammatory response may affect the patency and regeneration of vascular grafts. We also seek to determine the clinical potential of these VEGF-based A-TEVs in a large, pre-clinical animal model. Given the importance of the inflammatory response for tissue regeneration, our work may have broader implications for regenerative medicine. Our productivity during the last funding cycle (35 publications), the promising discoveries including mechanistic and translational studies that originated from our laboratory, and the excellent team of investigators that we assembled inspires confidence that the work can be carried out successfully in our laboratories.

抽象的心血管疾病是美国的首要死因。尤其是冠状动脉疾病是最常见的疾病，每年进行超过 350,000 例搭桥手术，据 AHA 估计，每年的总成本为 260 亿美元。使用天然的组织工程方法或合成支架，甚至无支架策略已经开发出功能性和可植入血管移植物已在小型和大型动物模型以及人体临床试验 1-12 中进行了测试。近来多年来，该领域一直专注于工程脱细胞（A）-TEV，作为一种潜在的替代方法，可能会提供现成的移植物用于治疗心血管疾病。近日，我们报道成功基于小肠粘膜下层 (SIS) 的 A-TEV 的开发，该 SIS 依次功能化肝素和血管内皮生长因子（VEGF-165，简称VEGF）13，14。该 A-TEV 已植入成功进入小型（小鼠）15 和大型（羊）动物模型 13 的动脉循环，证明收缩血管壁的通畅、内皮化和再生。有趣的是，VEGF 修饰的移植物充满了抗炎性 M2 巨噬细胞，而仅含有肝素的血管移植物则含有主要是 M1 型巨噬细胞 15。此外，含有 VEGF 的移植物具有类似于天然动脉与不含 VEGF（单独肝素）的移植物发生收缩，显得杂乱无章且缺乏良好的明确的内皮和血管壁。这促使我们假设 A-TEV 的成功再生体内可能依赖于产生抗炎和促再生环境，这可能是通过装饰移植物表面的固定化 VEGF (iVEGF) 进行调节（至少部分调节）。在本提案中，我们试图从三个具体目标来研究这一假设。在目标 1 中，我们将探索 VEGF 调节炎症反应的机制。在目标 2 中，我们将采用新颖的转基因小鼠模型监测单核细胞浸润移植物并研究 VEGF 信号传导的作用关于炎症和移植物再生。最后，在目标3中我们将探讨长期的通畅和重塑在大型临床前动物模型（绵羊）中使用 A-TEV 来评估这些移植物的临床潜力。这是一项高度创新的提案，旨在研究调节炎症反应如何可能影响血管移植物的通畅和再生。我们还试图确定这些的临床潜力基于 VEGF 的 A-TEV 在大型临床前动物模型中的应用。鉴于炎症反应的重要性对于组织再生，我们的工作可能对再生医学产生更广泛的影响。我们的生产力在上一个资助周期（35 篇出版物）中，有希望的发现包括机械和转化源自我们实验室的研究以及我们组建的优秀研究团队激发了人们的灵感我们相信这项工作能够在我们的实验室中成功开展。