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

• 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
• 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

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.

摘要 心血管疾病是美国人死亡的主要原因。尤其是冠状动脉疾病 是最常见的疾病，每年有超过35万例旁路移植手术， 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，甚至无支架的策略已经开发出功能性和可植入的血管， 已经在小型和大型动物模型以及人类临床试验1-12中测试的移植物。近几 多年来，该领域一直专注于工程化脱细胞（A）-TEV作为一种潜在的替代方法， 为心血管疾病的治疗提供现成的移植物。最近，我们报道了成功的 基于小肠粘膜下层（SIS）的A-TEV的开发 肝素和血管内皮生长因子（VEGF-165，表示为VEGF）13，14。这辆A-TEV被植入 成功地进入小型（小鼠）15和大型（绵羊）动物模型13的动脉循环，证明 开放性、内皮化和收缩血管壁的再生。有趣的是，VEGF修饰的移植物 由抗炎的M2巨噬细胞填充，而仅含肝素的血管移植物含有 主要是M1型巨噬细胞15.更重要的是，含有VEGF的移植物具有类似于 与没有VEGF（仅肝素）的移植物相比，自体动脉显得杂乱无章，缺乏良好的血管内皮细胞生长因子（VEGF）。 内皮和血管壁。这促使我们假设A-TEV的成功再生 在体内可能取决于产生抗炎和促再生环境， 通过修饰移植物表面的固定化VEGF（iVEGF）调节（至少部分）。 在这个提议中，我们试图在三个具体目标中研究这个假设。在目标1中，我们将探讨 VEGF调节炎症反应的机制。在目标2中，我们将使用新的 转基因小鼠模型，以监测单核细胞浸润到移植物中并研究VEGF信号传导的作用 对炎症和移植物再生的影响最后，在目标3中，我们将探讨长期通畅性和重塑 在大型临床前动物模型（绵羊）中观察A-TEV的变化，以评估这些移植物的临床潜力。 这是一个高度创新的建议，旨在研究如何调节炎症反应， 影响血管移植物的开放性和再生。我们还试图确定这些药物的临床潜力， 在大型临床前动物模型中的基于VEGF的A-TEV。鉴于炎症反应的重要性 对于组织再生，我们的工作可能会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），有前途的发现，包括机械和翻译 这些研究都来自我们的实验室，我们组建的优秀研究团队激发了 相信我们的实验室可以成功地进行这项工作。