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

项目摘要 组织工程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。 评价组织工程血管移植物（TEVG）在先天性心脏病中应用的临床试验结果 手术已经证明了TEVG的生长能力，使其成为第一个人造移植物， 潜力然而，这些试验的结果也表明，狭窄是最常见的移植物相关性 并发症和阻碍其广泛临床应用的原则障碍。最近我们发现了一本小说 由LYST基因编码的免疫调节蛋白。LYST基因的突变显著降低了 小鼠模型中TEVG狭窄的发生率。在这个建议中，我们将研究细胞和分子 LYST介导的TEVG狭窄形成的潜在机制。我们将使用按需诱导 LYST突变小鼠，以确定该过程的关键时间因素。接下来，我们将使用 阐明巨噬细胞作用并确定关键细胞类型的条件性LYST突变体模型 负责驱动LYST介导的TEVG狭窄。最后，我们将评估细胞外囊泡的作用- 依赖于细胞间信号传导的LYST介导的TEVG狭窄的形成。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 基于调节LYST功能。具有增长能力的改进的TEVG的开发具有 改善先天性心脏病患儿预后的潜力。

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.