GENETIC MODIFICATION OF THE HEART IN AGING AND DISEASE

衰老和疾病中心脏的基因改造

基本信息

批准号：
7404520
负责人：
JOSEPH Mark METZGER
金额：
$ 24.7万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2007-05-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7404520
关键词：
Accounting Adenovirus Vector Adenoviruses Adult Age-Months Aging Animals Buffers Calcium Cardiac Cardiac Myocytes Cardiomyopathies Cells Characteristics Clinical Treatment Congenital Heart Defects Country Cytoskeletal Proteins Dependovirus Disease Disease Progression Duchenne muscular dystrophy Dystrophin Elderly Family Functional disorder Gene Delivery Gene Transfer Generations Genetic Genetic Models Heart Heart failure Hereditary Disease Hospitalization Lead Length Modeling Modification Morbidity - disease rate Mus Muscle Cells Muscular Dystrophies Myocardial Myocardium Myopathy Organ Patients Performance Physiological Pump Relaxation Rodent Serotyping Specificity Striated Muscles Teenagers Testing United States Viral Vector Work age related clinically relevant gene transfer vector gutted adenoviral vector heart function hemodynamics in vivo juvenile animal mdx mouse mortality prevent therapeutic protein

项目摘要

Heart performance declines during aging and contributes to heart failure, the leading cause of combined morbidity and mortality in the United States. The mechanism of altered heart function during aging is not fully understood, although disturbances in myocyte intracellular calcium handling appear directly involved. Progressive, aging-dependent deficits in heart performance are also associated with various genetic diseases of striated muscle. In Duchene Muscular Dystrophy (DMD), the cytoskeletal protein dystrophin is absent and results in mild cardiac abnormalities early in disease progression. However, heart dysfunction in DMD is markedly aggravated by aging such that by the late teen years most patients have clinically relevant cardiomyopathy. Heart failure accounts for at least 10% of the mortality in DMD. There are no clinical treatments available to directly prevent, halt or correct heart failure associated with aging or DMD. This proposal is focused on determining the capability of viral vectors to systematically express potential therapeutic proteins in the old and diseased heart in vivo. The proposal's unifying hypothesis is that genetic modification of cardiac muscle by viral vectors in vivo will prevent or reverse myocardial performance dysfunction in old animals, and in a model of progressive cardiac muscle disease (mdx mice). The Specific Aims are to test the following hypotheses: 1. Gutted adenoviral gene transfer, and to a lesser extent rAAV (both serotypes 2 and 6) gene transfer, will overcome the decreased efficiency and stability of cardiac gene transfer in old animals obtained with first generation adenoviral vectors in vivo. 2. Gutted adenoviral gene transfer, and to a lesser extent rAAV gene transfer (both serotypes 2 and 6), of intracellular calcium buffers and pumps to the old heart will attain long-term (months) and physiological levels of expression, and reverse the slowed myocardial relaxation characteristic of old animals in vivo. 3. Gutted adenoviral vectors harboring full length dystrophin will lead to efficient gene transfer, expression, and cytoskeletal localization of dystrophin in adult cardiac myocytes from dystrophic (mdx) mice, and restore both myocyte contractile function and heart organ hemodynamics in vivo.

心脏表现在衰老期间下降，并导致心力衰竭，这是美国发病率和死亡率综合的主要原因。衰老过程中心脏功能改变的机制尚不完全了解，尽管心肌细胞内钙处理的障碍似乎直接涉及。渐进的，依赖衰老的心脏表现缺陷也与横纹肌的各种遗传疾病有关。在Duchene肌肉营养不良（DMD）中，缺乏细胞骨架蛋白肌营养不良蛋白，并在疾病进展的早期导致轻度心脏异常。但是，DMD中心脏功能障碍因老化而明显加剧，使得大多数患者在临床上具有相关心肌病。心力衰竭占DMD死亡率的至少10％。没有可直接预防，停止或正确的与衰老或DMD相关的心力衰竭的临床治疗方法。该建议的重点是确定病毒载体在体内旧心脏和患病心脏中系统地表达潜在的治疗蛋白的能力。该提案的统一假设是，病毒载体在体内对心脏肌肉的遗传修饰将预防或逆转旧动物的心肌功能障碍，以及进行性心脏肌肉疾病（MDX小鼠）的模型。具体目的是检验以下假设：1。肠道病毒基因转移，在较小程度上RAAV（均均为血清型2和6）基因转移，将克服心脏基因的效率和稳定性的降低和稳定性在体内用第一代腺病毒载体获得的老动物中的转移。 2。肠内基因转移的肠内基因转移，在较小程度上，细胞内钙缓冲液和泵向旧心脏的钙化基因转移（血清型2和6）将长期（月份）表达的长期（月份）表达水平，并扭转较慢的心肌宽松特征，使旧动物的旧动物属于Vivo。 3。具有全长肌营养不良蛋白的沟渠腺病毒载体将导致从营养不良（MDX）小鼠的成人心脏肌细胞中肌营养不良蛋白的有效基因转移，表达和细胞骨架定位，并恢复两种肌细胞收缩功能和心脏器官血液动力在Vivo中。