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Genetic Engineering of Vein Bypass Grafts in Vascular and Cardiovascular Surgery

血管和心血管手术中静脉搭桥移植物的基因工程

基本信息

批准号：
7340551
负责人：
FRANK W LOGERFO
金额：
$ 50.97万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7340551
关键词：
Anastomosis - action Arteries Biology Blood Vessels Bypass Candidate Disease Gene Canis familiaris Cardiopulmonary Bypass Cardiovascular Surgical Procedures Cardiovascular system Cells Cicatrix Clinical Condition Coronary Restenosis Data Development Endothelial Cells Endothelium Event Extracellular Matrix Failure Gene Expression Gene Silencing Gene Targeting Genes Genetic Genetic Engineering Goals Hematopoietic Hyperplasia In Vitro Inflammatory Injury Intervention Lasers Lead Lesion Medial Mediating Methods Microscopy Modeling Molecular Operating Rooms Operative Surgical Procedures Pathogenesis Pathologic Processes Peripheral Vascular Diseases Phenotype Prosthesis RNA Interference Research Personnel Reverse Transcriptase Polymerase Chain Reaction Smooth Muscle Smooth Muscle Myocytes Stenosis Surgical Injuries System Techniques Technology Therapeutic Therapeutic Uses Thinking Time Tissues Transfection Transplantation Validation Veins Western Blotting gene therapy graft failure human disease human tissue implantation in vivo migration novel therapeutics precursor cell pressure prevent response response to injury

项目摘要

DESCRIPTION (provided by applicant): Intimal hyperplasia in arterialized vein bypass grafts is a significant cause of vein graft stenosis and delayed graft failure. Injury at the time of implantation or as a consequence of transplantation into the high pressure arterial system may contribute to these delayed events. Alterations in gene expression accompany implantation and arterialization injury. These alterations lead to intimal hyperplasia, including transformation of endothelial cells to an inflammatory state and initiating migration and transformation of smooth muscle cells from the contractile to secretory states thus creating the lesion of intimal hyperplasia. It is our hypothesis that silencing of genes upregulated by injury to the vein wall will diminish intimal hyperplasia. Furthermore, gene silencing can be accomplished within the constraints of operating room conditions. Our preliminary data demonstrates our ability to identify candidate genes associated with intimal hyperplasia and our ability to knockdown gene expression with siRNA. Using laser capture microscopy we have separated genetic events in the endothelium from those in smooth muscle. In the proposed study we will apply these technologies to (1) systematically identify silencing targets, (2) to silence target genes in vitro, (3) to silence target genes under surgical conditions, (4) to demonstrate inhibition of intimal hyperplasia in vein grafts in vivo. Both human tissue and canine models will be used as well as all cultures, microarrays, laser capture, RT-PCR, Western Blot, and related technology. This study will greatly strengthen the application of gene silencing to clinical problems in vascular surgery, and broaden our understanding of vascular wall biology. Public Lay Summary: Scar tissue formation due to surgical injury is a major cause for failure of heart bypass grafts and bypass grafts for peripheral vascular disease. The investigators propose to prevent formation of this scar tissue by controlling expression of the genes that cause it, using techniques that can be applied in the operating room.

描述（由申请人提供）：动脉化静脉旁路移植物中的内膜增生是静脉移植物狭窄和延迟移植物失效的重要原因。植入时的损伤或移植到高压动脉系统的结果可能导致这些延迟事件。基因表达的改变伴随着床和动脉化损伤。这些变化导致内膜增生，包括内皮细胞转化为炎症状态，并启动平滑肌细胞从收缩状态迁移和转化为分泌状态，从而造成内膜增生病变。我们的假设是，沉默因静脉壁损伤而上调的基因将减少内膜增生。此外，基因沉默可以在手术室条件的限制内完成。我们的初步数据表明，我们有能力确定与内膜增生相关的候选基因，我们有能力敲低基因表达的siRNA。使用激光捕获显微镜，我们已经分离的遗传事件在内皮细胞从那些在平滑肌。在拟议的研究中，我们将应用这些技术（1）系统地鉴定沉默靶点，（2）体外沉默靶基因，（3）在手术条件下沉默靶基因，（4）证明体内抑制静脉移植物内膜增生。将使用人体组织和犬模型以及所有培养物、微阵列、激光捕获、RT-PCR、蛋白质印迹和相关技术。本研究将大大加强基因沉默在血管外科临床问题中的应用，并拓宽我们对血管壁生物学的理解。Public Lay摘要：手术损伤引起的瘢痕组织形成是心脏旁路移植术和外周血管疾病旁路移植术失败的主要原因。研究人员建议通过控制导致疤痕的基因的表达来防止疤痕组织的形成，使用可以在手术室中应用的技术。