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：
10599990
负责人：
christopher Kane breuer
金额：
$ 64.16万
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/10599990
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 Endosomes Endothelial Cells Goals Growth Immune Immune response Immunosuppression Implant In Vitro Incidence Infiltration Inflammation Live Birth Macrophage 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 Tissues Transgenic Organisms Tubular formation Vascular Graft Vesicle Wild Type Mouse 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 man mortality mouse model mutant next generation novel operation prevent rational design 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生物材料用于先天性心脏手术提供了一种策略。我们评估先天性心脏中组织工程血管移植物（TEVG）使用的临床试验的结果手术证明了TEVG的增长能力，使其成为第一个随着生长的嫁接潜在的。但是，这些试验的结果也表明狭窄是最常见的移植物相关的并发症和主要障碍阻止其广泛的临床使用。最近，我们确定了一本小说由Lyst基因编码的免疫调节蛋白。 Lyst基因的突变大大降低了鼠模型中TEVG狭窄的发生率。在此提案中，我们将研究细胞和分子 Lyst介导的TeVG狭窄形成的基础机制。我们将使用按需诱导的 lyst突出小鼠以确定该过程构成的关键时间因素。接下来，我们将使用有条件的突出模型以阐明巨噬细胞的作用并确定关键细胞类型负责驱动Lyst介导的TEVG狭窄。最后，我们将评估细胞外囊泡的作用依赖性细胞间信号传导对LYST介导的TEVG狭窄的形成。成功完成这些研究将为抑制Tevg狭窄的形成的合理设计策略打开大门基于调制LYST函数。具有增长能力的提高TEVG的发展具有改善先天性心脏病的儿童的预后潜力。