Elucidating the Molecular Mechanisms Underlying LYST-mediated Tissue Engineered Vascular Graft Stenosis

项目总结 组织工程学为开发更好的用于先天性心脏病手术的生物材料提供了一种策略。 组织工程血管移植物(TEVGs)在先天性心脏病中应用的临床试验结果 手术证明了TEVG的生长能力，使其成为第一个具有生长能力的人造移植物 潜力。然而，这些试验的结果也显示，狭窄是最常见的移植物相关因素。 并发症和阻碍其临床广泛应用的主要障碍。最近，我们确定了一部小说 由Lyst基因编码的免疫调节蛋白。Lyst基因的突变极大地降低了 TEVG狭窄在小鼠模型中的发生率。在这个提案中，我们将研究细胞和分子 Lyst介导的TEVG狭窄形成的机制。我们将使用按需感应式 Lyst-突变小鼠来确定这一过程背后的关键时间因素。接下来，我们将使用 阐明巨噬细胞作用并确定临界细胞类型的条件溶血-突变模型(S) 负责推动Lyst介导的TEVG狭窄。最后，我们将评估细胞外小泡的作用- 细胞间信号在Lyst介导的TEVG狭窄形成中的依赖。成功完成 这些研究将为合理设计抑制TEVG狭窄形成的策略打开大门 基于调制Lyst函数。改进的具有增长能力的TEVG的开发具有 有可能改善先天心脏病儿童的预后。

PROJECT SUMMARY Tissue engineering provides a strategy for developing better biomaterials for use in congenital heart surgery. Results of our clinical trials evaluating the use of tissue engineered vascular grafts (TEVGs) in congenital heart surgery have demonstrated the growth capacity of the TEVG making it the first man made graft with growth potential. However, results of these trials have also revealed that stenosis is the most common graft-related complication and the principle hurdle preventing its widespread clinical use. Recently, we have identified a novel immune-regulatory protein encoded by the LYST gene. Mutations of the LYST gene dramatically reduce the incidence of TEVG stenosis in murine models. In this proposal, we will investigate the cellular and molecular mechanisms underlying the formation of LYST-mediated TEVG stenosis. We will use a on-demand inducible LYST-mutant mouse to determine the critical temporal factors underling this process. Next, we will use a conditional LYST-mutant model to elucidate the roles of macrophages and determine the critical cell type(s) responsible for driving LYST-mediated TEVG stenosis. Finally, we will evaluate the role of extracellular vesicle- dependent intercellular signaling on the formation of LYST-mediated TEVG stenosis. Successful completion of these studies would open the door to rationally designing strategies to inhibit the formation of TEVG stenosis based on modulating LYST function. The development of an improved TEVG with growth capacity has the potential to improve outcomes for children born with congenital heart disease.