GENE AND STEM CELL THERAPY IN CORONARY ARTERY BYPASS GRAFT

冠状动脉搭桥术中的基因和干细胞治疗

基本信息

批准号：
8913536
负责人：
Devendra K. Agrawal
金额：
$ 72.58万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-13 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913536
关键词：
Affect Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Anterior Anti-Inflammatory Agents Anti-inflammatory Aortic coarctation Area Arterial Fatty Streak Arteries Atherosclerosis Autologous Blood Vessels Bypass CCL2 gene Caliber Cardiology Cardiovascular system Cell Proliferation Cell Therapy Cellular biology Cessation of life Clinical Clinical Research Coronary Coronary Angiography Coronary Arteriosclerosis Coronary Artery Bypass Coronary artery Development Disease Echocardiography Electrocardiogram Endothelial Cells Endothelium Engineering Epigastric Epoprostenol Event Extracellular Matrix Failure Family suidae Gene Delivery Gene Expression Genes Growth Factor Heart Heparin Human Hyperplasia In Vitro Inflammation Inflammatory Insulin-Like Growth Factor I Investigation Laboratories Left Lipids Mammary gland Mediator of activation protein Mesenchymal Stem Cells Mitogens Modeling Molecular Molecular Biology Monitor Morbidity - disease rate Myocardial Infarction Natural regeneration Operative Surgical Procedures Outcome PTEN gene Pathology Pathway interactions Patients Phosphoric Monoester Hydrolases Positioning Attribute Pump Radiation Recording of previous events Research Resolution Saphenous Vein Side Smooth Muscle Myocytes Solutions Stenosis System TIMP3 gene Techniques Tenascin Testing Therapeutic Thick Thrombosis Tissue Inhibitor of Metalloproteinase-3 Touch sensation Transgenes Translating Treatment Efficacy Ulcer Veins Wit Work adverse outcome ascending aorta cell growth cytokine gene therapy graft failure heart function high risk human disease injured intercellular communication internal thoracic artery intima media mortality novel overexpression phase 1 study prevent public health relevance receptor expression repaired response to injury restenosis shear stress stem cell therapy tomography transgene expression vector

项目摘要

DESCRIPTION (provided by applicant): Saphenous vein (SV) graft failure is a common clinical problem in patients undergoing coronary artery bypass graft (CABG) surgery. Underlying mechanisms are still unclear. Failure of various therapies, including targeted gene therapy, could be due to the bad choice of the gene and/or the use of animal model dissimilar to human disease. Also, there was no consideration to promote endothelial cell proliferation. We observed inactivation of PTEN with increased proliferation of SMCs in human SV and PTEN overexpression limits cell proliferation. Since PTEN modulates cell signaling and cell growth, PTEN transgene expression in SV graft SMCs would prevent the development of intimal hyperplasia. Also, the repair of endothelial cells (ECs) with mesenchymal stem cells (MSCs) would inhibit thrombosis. The hypothesis is that the inhibition of intimal hyperplasia by PTEN transgene while preserving endothelium with the delivery of MSCs in autologous vein grafts prior to CABG would be the best strategy to maintain vein graft patency. We will do these studies in a well-established and routinely used in our laboratory the swine model of atherosclerosis and perform CABG using superficial epigastric vein (SEV) isolated with "no touch technique". Aim 1: Our hypothesis predicts that the overexpression of PTEN transgene in the SMCs of vein graft in coronary arteries in atherosclerotic swine will prevent the development of neointimal hyperplasia in bypass vein graft. Aim 2: Our hypothesis predicts that the repair of endothelial cells with MSCs together with PTEN transgene in the SMCs of vein graft in coronary arteries of atherosclerotic swine will prevent thrombosis and neointimal hyperplasia in bypass vein graft, and this would be superior to the effect of PTEN transgene alone. Aim 3: Our hypothesis predicts that overexpression of PTEN transgene and MSCs-induced endothelial cell regeneration would reduce inflammation and inhibit constrictive remodeling together with inhibition of neointimal hyperplasia in the vein graft in coronary arteries. The autologous SEV will be exposed to PTEN vector and MSCs followed by aorto-coronary grafting in atherosclerotic swine. EKG and echocardiography to monitor heart function, and coronary angiography and optimal coherence tomography to quantify in-segment minimal luminal diameter, diameter stenosis, late loss and intimal hyperplasia will examine the therapeutic efficacy of this therapy. Histological parameters will include the intimal thickness, lumen area, intima-media ratio, development and ulceration of plaque, thrombosis, extracellular matrix, and re-occlusion. Expression of pro- and anti-inflammatory and pro-hyperplasia pathways will be examined in excised vein graft and correlated with the degree of neointimal hyperplasia and constrictive remodeling. Findings from these studies will provide the conceptual support for our hypothesis, and position us to translate our investigation into a clinical phase 1 study for the use of PTEN-engineered autologous MSCs for the treatment and possibly cure of the vein graft disease following CABG.

描述（由申请人提供）：隐静脉（SV）移植失败是接受动脉旁路移植（CABG）手术的患者的常见临床问题，各种治疗（包括靶向基因治疗）的失败可能是由于。基因选择不当和/或使用与人类疾病不同的动物模型。此外，我们观察到 PTEN 失活导致人类 SV 和 SMC 增殖增加。 PTEN 过度表达限制细胞增殖，因此 SV 移植 SMC 中的 PTEN 转基因表达将阻止内膜增生的发生，而且间充质干细胞 (MSC) 修复内皮细胞 (EC) 会抑制血栓形成。假设在 CABG 之前通过自体静脉移植物中输送 MSC 来抑制 PTEN 转基因抑制内膜增生，同时保留内皮细胞，我们将在我们实验室常用的动脉粥样硬化猪模型中进行这些研究，并使用“无接触技术”分离的腹壁浅静脉 (SEV) 进行 CABG。：我们的假设预测，动脉粥样硬化猪冠状动脉静脉移植物的 SMC 中 PTEN 转基因的过度表达将阻止旁路静脉移植物中新内膜增生的发展。目的 2：我们的假设预测，用 MSC 联合 PTEN 转基因修复动脉粥样硬化猪冠状动脉静脉移植物的 SMC 中的内皮细胞，可预防旁路静脉移植物中的血栓形成和新生内膜增生，且效果优于单独的 PTEN 转基因：我们的假设预测 PTEN 转基因的过度表达和 MSC 诱导的内皮细胞再生将减少炎症并抑制。将自体 SEV 暴露于 PTEN 载体和 MSC，然后在动脉粥样硬化猪中进行收缩性重塑并抑制新内膜增生，然后进行心电图和超声心动图监测心脏功能，并进行冠状动脉造影和优化。用于量化节段内最小管腔直径、直径狭窄、晚期丢失和内膜增生的相干断层扫描将检查治疗效果该疗法的组织学参数包括内膜厚度、管腔面积、内膜-中膜比例、斑块的形成和溃疡、血栓形成、细胞外基质以及促炎和促增生途径的表达。将在切除的静脉移植物中进行检查，并与新内膜增生和收缩重塑的程度相关。这些研究的结果将为我们的假设提供概念支持，并使我们能够将我们的研究转化为临床阶段。一项使用 PTEN 工程化自体 MSC 治疗和可能治愈 CABG 后静脉移植疾病的研究。