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

阐明 LYST 介导的组织工程血管移植狭窄的分子机制

基本信息

批准号：
10378148
负责人：
christopher Kane breuer
金额：
$ 66.86万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10378148
关键词：
Affect Autologous Automobile Driving Biocompatible Materials Blood Vessel Prosthesis Blood Vessels CHS1 gene Cardiac Surgery procedures Cardiovascular system Cause of Death Cell physiology Cells Child Clinical Clinical Research Clinical Trials Code Complication Computer Models Congenital Abnormality Congenital Heart Defects Development Endothelial Cells Goals Growth Immune Immune response Immunosuppression Implant In Vitro Incidence Infiltration Inflammation Live Birth Mediating Medical Messenger RNA MicroRNAs Modeling Molecular Morbidity - disease rate Mus Mutant Strains Mice Mutation Newborn Infant Operative Surgical Procedures Paracrine Communication Postoperative Period Procedures Process Production Proteins Public Health Regulator Genes Role Safety Serious Adverse Event Signal Transduction Smooth Muscle Myocytes Source Stenosis Surgical complication System Tamoxifen Therapeutic Tissue Engineering Transgenic Organisms Tubular formation Vascular Graft Vesicle Wild Type Mouse base cell type congenital heart disorder cost critical period design disability extracellular vesicles functional restoration genetic regulatory protein graft function heart valve replacement immunoregulation implantation improved improved outcome in vivo macrophage man mortality mouse model mutant next generation novel operation prevent rational design reconstruction repaired scaffold vascular tissue engineering

项目摘要

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.

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。在本提案中，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。