A novel inotropic gene therapy approach for aging induced cardiac dysfunction

一种治疗衰老引起的心功能障碍的新型正性肌力基因治疗方法

• 批准号: 9182534
• 负责人: Jonathan Paul Davis
• 金额: $ 23.1万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182534
• 关键词: Adult; Age-Months; Aging; Angiotensin II; Apoptosis; Arrhythmia; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cessation of life; Data; Defect; Dependovirus; Development; Dimensions; Echocardiography; Electrocardiogram; Exercise Tolerance; Failure; Fibrosis; Formulation; Functional disorder; Heart; Heart failure; Histology; Hormones; Hypertension; Hypertrophy; Individual; Infusion procedures; Life; Measures; Mediating; Mus; Myocardial dysfunction; Myocardium; Performance; Preventive measure; Property; Protein Engineering; Proteins; Public Health; Quality of life; Relaxation; Risk; Risk Factors; Serotyping; Testing; Therapeutic; Troponin C; VO2max; age related; aged; gene therapy; heart dimension/size; heart function; improved; in vivo; mouse model; novel; novel strategies; pressure; prevent; senescence; treatment strategy

Cardiovascular disease is the number one cause of death in the US (e.g., heart failure); with aging and hypertrophy the two foremost risk factors. Aging increases the cardiac afterload and decreases contractile reserve that eventually compromise heart function. This sets up a vicious cycle (contractile defects↔remodeling↔compromised heart function) that spirals the heart toward failure culminating in death. Inotropic strategies to increase contractility have been developed to aid the heart. This inotropic support will break this vicious cycle to avert the development of heart failure to preserve life and the quality of life (healthspan). Unfortunately, current inotropic strategies are confounded by increasing cytosolic Ca2+, compromising relaxation, and/or causing arrhythmias which accelerates the spiral into heart failure and hastens death. We have a novel approach to increase inotropy without the deleterious effects of existing inotropes. Using the strengths of smartly formulating proteins, we have shown that cardiac contractility and contractile reserve can be directly controlled and strongly influenced by manipulating the Ca2+ dependent switch in cardiac muscle, troponin C (TnC). Our pioneering construct, L48Q TnC, is a strong Ca2+ sensitizer with properties of an ideal positive inotrope. Our preliminary results clearly demonstrate that the in vivo expression of L48Q TnC increases cardiac contractility and contractile reserve without any deleterious effects associated with other inotropic strategies. The objective of this proposal is to determine the cardiac effects of L48Q TnC in the senescent or hypertrophic mouse. We hypothesize that L48Q TnC will increase contractile reserve to improve heart function and aid cardiac performance during aging or hypertrophy. Excitingly, our preliminary data support our hypothesis in that L48Q TnC transduced mice (via Adeno Associated Virus serotype 9 - AAV9) maintain better cardiac performance upon aging or in hypertrophic mice. We will test our central hypothesis by pursuing the following aims: Aim 1- assess if L48Q TnC can improve cardiac performance of aging mice; Aim 2- assess if L48Q TnC can maintain cardiac performance in hypertrophy. Our notable preliminary findings demonstrate that the compromised cardiac performance of hypertrophy and senescent mice can be prevented by L48Q TnC. These data strongly support that L48Q TnC is an ideal positive inotrope (i.e., no deleterious effects) that can aid the heart in breaking the vicious cycle that spirals into heart failure and death. These studies will provide a new direction (i.e., inotropic support via L48Q TnC) that can be used therapeutically to enhance heart function in a variety of cardiomyopathies associated with aging

心血管疾病是美国的头号死因（例如，心力衰竭）;随着年龄的增长， 肥大是两个最重要的风险因素。衰老增加了心脏后负荷， 最终会损害心脏功能。这就形成了一个恶性循环（收缩 参与性重塑参与性心脏功能受损）使心脏逐渐衰竭，最终导致死亡。 已开发出增强收缩力的变力策略来帮助心脏。这种正性肌力支持将 打破这种恶性循环，避免心力衰竭的发展，以保护生命和生活质量 （healthspan）。不幸的是，目前的正性肌力策略被增加的胞质Ca 2+混淆， 损害放松和/或引起心律失常，从而加速进入心力衰竭， 加速死亡。我们有一种新的方法来增加收缩力，而没有现有的有害影响。 正性肌力药利用巧妙地配制蛋白质的优势，我们已经表明，心肌收缩力和 收缩储备可以直接控制和强烈的影响，通过操纵钙依赖 心肌肌钙蛋白C（TnC）。我们的开创性构建体L48 Q TnC是一种强Ca 2+敏化剂 具有理想的正性肌力药的特性。我们的初步结果清楚地表明，在体内 L48 Q TnC的表达增加心脏收缩力和收缩储备而没有任何有害作用 与其他正性肌力策略相关。本提案的目的是确定以下物质对心脏的影响 L48 Q TnC在衰老或肥大小鼠中的表达。我们假设L48 Q TnC会增加收缩性心肌炎， 储备，以改善心脏功能，并帮助心脏性能在老化或肥大。令人兴奋的是，我们 初步数据支持我们的假设，即L48 Q TnC转导的小鼠（通过腺相关病毒 血清型9 -AAV 9）在衰老时或在肥大小鼠中维持更好的心脏性能。我们将测试我们的 目标1-评估L48 Q TnC是否可以改善心脏功能 目的2-评估L48 Q TnC是否可以在肥大中维持心脏性能。我们 值得注意的初步研究结果表明，心脏肥大和 L48 Q TnC可预防小鼠衰老。这些数据强烈支持L48 Q TnC是理想的 正性肌力药（即，没有有害影响），可以帮助心脏打破恶性循环， 心力衰竭和死亡。这些研究将提供一个新的方向（即，通过L48 Q TnC的正性肌力支持）， 可在治疗上用于增强与衰老相关的各种心肌病的心脏功能