Cell Therapy in Hypertrophied and Remodeled Left Ventricle

左心室肥大和重塑的细胞疗法

基本信息

批准号：
9391517
负责人：
Jianyi Zhang
金额：
$ 64.65万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-10 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9391517
关键词：
ATP Hydrolysis Alabama Allografting Animals Antigens Arrhythmia Bioenergetics Blood Vessels Cardiac Cardiac Myocytes Cell Differentiation process Cell Line Cell Therapy Cell Transplantation Cell Transplants Cells Chest Cicatrix Clinic Clinical Connexin 43 Connexins Creatine Kinase Diagnostic Donor person Early Diagnosis Electrocardiogram Electrophysiology (science)Endothelial Cells Engraftment Family suidae Functional disorder Future Genes Graft Survival HLA Antigens Heart Heart Atrium Heart failure Histocompatibility Antigens Class I Human Human Engineering Hypertrophy Immune system Implant In Vitro Infarction Injection of therapeutic agent Knock-out Lead Left Ventricular Remodeling Magnetic Resonance Spectroscopy Measures Mechanics Mediating Methods Mitochondria Modality Modeling Mole the mammal Monitor Muscle Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardial tissue Myocardium NMR Spectroscopy Noise Optics Patients Performance Perfusion Phosphocreatine Preparation Proteins Reporting Risk Safety Signal Transduction Smooth Muscle Myocytes Spectrum Analysis Stress Stretching Surface System T-Lymphocyte Techniques Technology Testing Therapeutic Thick Tissues Transplantation Universities Ventricular allograft rejection base design electrical property experimental study functional outcomes immunosuppressed improved in vivo induced pluripotent stem cell inorganic phosphate insight mechanical properties nonhuman primate novel overexpression prevent protein expression stem cell therapy technology validation

项目摘要

Cell Therapy in Hypertrophied and Remodeled Left Ventricle ABSTRACT The recent report of increased arrhythmic potential in hearts of non-human primates that received cell therapy causes serious concerns in field of cardiac stem cell therapy. Although the beneficial effects of human induced pluripotent stem cell (hiPSC) cellular therapy in hearts with post myocardial infarction (MI) have been recently reported in large animal studies, there could be additional benefits in applying a highly functional prefabricated cardiac muscle tissue equivalent over the MI surface. The specific aims (SA) are: SA1. To fabricate the larger and thicker human cardiac muscle patch (hCMP) using the hiPSC - cardiomyocytes (CM), - smooth muscle cells (SMC) and – endothelial cells (EC). We will fabricate a new type of larger and thicker hCMP and characterize its vascular, electrical, and mechanical properties in vitro. To increase the engraftment rate, we will generate hiPSC lines by engineering the hiPSC, in which human HLA Class I and/or Class II protein expression have been knocked out (HLA-KO -hCMP) by the gene editing technology. To reduce the arrhythmogenic potential, we will generate hiPSC lines by engineering the hiPSC to overexpress the gap junction protein: Cx43 (Cx43-hCMP). SA2. Using an immuno-suppressed porcine model of post-infarction LV remodeling, we will examine whether the transplantation of a prefabricated hCMP will result in better functional outcomes in reductions in LV scar bulging and wall stress, and improvements in myocardial bioenergetics and contractile function as compared to standard cell injection. We will compare the electrical stability of hearts with or without hCMP transplantation by continuously monitoring ECG for 8 weeks in vivo, and by conducting ex vivo dual optical mapping studies of electrical propagation. We will develop the completely non-invasive NMR technology that will provide unprecedented levels of sensitivity and signal-to-noise ratio (SNR) for P-31 NMR spectroscopy measuring the myocardial ATP hydrolysis rate with a precision of micro moles/s per gram of myocardium in a large bore magnet, which can be applied clinically. The findings of the studies will advance our understanding of the mechanisms of functional benefits of cell therapy in hearts with post-infarction LV remodeling, which can lead to better diagnostic and therapeutic modalities for CHF patients.

肥厚和重塑的左心室的细胞疗法抽象的最近关于接受细胞疗法的非人类素质心脏心脏心律失常增加的报告引起心脏干细胞疗法领域的严重关注。尽管人类诱导的有益影响最近，心肌梗死（MI）心脏中的多能干细胞（HIPSC）细胞疗法已最近已成为在大型动物研究中报道，应用高功能性预制可能还有其他好处心肌组织等效于MI表面。具体目的（SA）为：SA1。制造较大的使用hipsc -symyocytes（cm）， - 平滑肌，人类心脏肌肉斑块（HCMP）较厚细胞（SMC）和 - 内皮细胞（EC）。我们将制造一种新型的较大和较厚的HCMP，并且在体外表征其血管，电和机械性能。为了提高植入率，我们将通过设计HIPSC来生成HIPSC线，其中人HLA I类和/或II类蛋白表达已被基因编辑技术拆除（HLA -KO -HCMP）。减少心律失常的潜力，我们将通过工程hipsc过表达间隙来产生HIPSC线连接蛋白：CX43（CX43-HCMP）。 SA2。使用接口后LV的免疫抑制猪模型重塑，我们将检查预制的HCMP的移植是否会导致更好的功能 LV疤痕隆起和壁压力减少的结果，以及心肌生物能学和改善与标准细胞注射相比，收缩功能。我们将比较心脏的电稳定性通过连续监测ECG 8周，并通过进行HCMP移植，并进行离体双光学映射研究的电繁殖。我们将发展完全无创的 NMR技术将为P-31提供前所未有的灵敏度和信噪比（SNR） NMR光谱法测量心肌ATP水解速率，精度为微痣/S每克在大孔中的心肌，可以在临床上施用。研究结果将进步我们对患有肠道后LV心脏中细胞疗法功能益处的功能益处机制的理解重塑，可以为CHF患者提供更好的诊断和治疗方式。