CARDIAC GENE THERAPY

心脏基因治疗

• 批准号: 7266263
• 负责人: H Lee Sweeney
• 金额: $ 42.16万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7266263
• 关键词: BCL2 gene /protein; adeno associated virus group; apoptosis; biotechnology; calcium flux; cardiac myocytes; cardiovascular disorder therapy; cytoprotection; gene therapy; genetically modified animals; heart failure; hepatocyte growth factor; idiopathic dilated cardiomyopathy; laboratory mouse; laboratory rabbit; myocardial infarction; nonhuman therapy evaluation; pathologic process; transfection /expression vector; tropomyosin; troponin

The proposed research seeks to delineate the mechanisms underlying the progressive development of dilated cardiomyopathy and failure following myocardial infarction. We also will examine resetting of the calcium set point for contractility as a potential strategy to blunt hypertrophic drive resulting from pressure overload. In doing so, we will evaluate AAV-gene transfer approaches for the treatment of heart failure. First we will evaluate the hypothesis that an apoptotic component drives the dilated cardiomyopathy that follows focal infarction. The stimulus arises from stretch that is imposed on the border zone cells following rigidification of the infarct zone. Continuous inhibition of cell death is necessary to prevent the development of dilated failure. The ability of overexpression of the anti-apoptosis factors Bcl-2, hepatocyte growth factor (HGF) and dominant negative phospholamban to impact the development of dilated cardiomyopathy will be tested. In addition, we will analyze these transgenes and a novel transgene (arginine kinase) in a mouse model of atherosclerosis, in which there is global ischemia and focal infarction. Lastly, we will alter the calcium sensitivity of the cardiac troponin complex in an attempt to blunt pressure overload hypertrophy and the subsequent progression to failure.

拟议的研究旨在阐明扩张型心肌病逐渐发展和心肌梗死后衰竭的潜在机制。我们还将研究重置收缩性钙设定点，作为减弱压力超负荷导致的肥大驱动力的潜在策略。在此过程中，我们将评估治疗心力衰竭的 AAV 基因转移方法。首先，我们将评估细胞凋亡成分驱动局灶性梗塞后扩张型心肌病的假设。刺激来自于边界区细胞僵化后的拉伸。 梗塞区。持续抑制细胞死亡对于防止扩张衰竭的发生是必要的。将测试抗凋亡因子 Bcl-2、肝细胞生长因子 (HGF) 和显性失活受磷蛋白的过度表达影响扩张型心肌病发展的能力。此外，我们将在动脉粥样硬化小鼠模型中分析这些转基因和新的转基因（精氨酸激酶），其中存在全身缺血和局灶性梗塞。最后，我们将改变心肌肌钙蛋白复合物的钙敏感性，试图阻止压力超负荷肥大和随后的衰竭进展。