Synergistically Target Mitochondria for Heart Failure Treatment

协同靶向线粒体治疗心力衰竭

基本信息

批准号：
10584938
负责人：
Lufang Zhou
金额：
$ 61.12万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584938
关键词：
Adenoviruses Affect American Animal Model Animals Antioxidants Biochemical Biodistribution Bioluminescence Calcium Cardiac Cardiac Myocytes Cause of Death Cell Survival Cell physiology Cessation of life Clinic Complex Cytoprotection Cytosol Data Defect Development Dilated Cardiomyopathy Dose Drug Kinetics Equilibrium Family suidae Functional disorder Future Genes Goals Heart Heart Mitochondria Heart failure Histologic Histopathology Homeostasis Human Immune response Immunity Inner mitochondrial membrane Ischemia Light Lighting Liver Luciferases Mediating Membrane Potentials Metabolic Pathway Mitochondria Modeling Molecular Mus Myocardial Ischemia Myocardial Reperfusion Injury Myocardial dysfunction Names Organ Outcome Oxidation-Reduction Pathogenesis Pathologic Patients Phenylephrine Play Production Proton Pump Publishing Quality Control Reactive Oxygen Species Regulation Renilla Reperfusion Injury Reperfusion Therapy Rhodopsin Role Safety Satellite Viruses Signal Pathway Stress Survival Rate Technology Therapeutic Toxic effect Toxicology Translations Treatment Efficacy Treatment Failure Ventricular Whole Blood cell injury clinical translation cytotoxicity dosage efficacy evaluation heart function improved in vivo innovation innovative technologies light gated luciferin mitochondrial dysfunction mitochondrial membrane mortality mouse model mutant myocardial damage neutralizing antibody novel novel therapeutic intervention optogenetics pre-clinical preclinical study preservation pressure redshift synergism targeted treatment therapeutic target tool transduction efficiency translational potential translational therapeutics treatment strategy

项目摘要

SUMMARY/ABSTRACT Heart failure (HF) is a leading cause of death worldwide. Although the pathophysiology of HF is complex and remains incompletely understood, defects in mitochondrial function have been implicated in the progression and outcomes of HF, and emerged as an important target for HF therapy. One well-known contributing factor to adverse cardiac remodeling in the failing hearts is excess mitochondrial-derived reactive oxygen species (mtROS). Accordingly, a variety of antioxidant-based therapies have been developed for HF treatment over the last decades. However, despite promising outcomes in preclinical studies, translation of these therapies to the clinic has not succeeded to date, suggesting that alternative or complementary mitochondrial therapeutic targets are needed. In addition to excess mtROS, profound loss of mitochondrial membrane potential (m) is another key hallmark of HF. In the cardiomyocyte (CM), m disruption affects not only energy production, but also a variety of signaling pathways crucial for cell function and survival, such as redox balance, calcium homeostasis and mitochondrial quality control. We hypothesize that synergistically targeting mitochondria, i.e., concurrently preserving mitochondrial m and scavenging excess mtROS, is a viable therapeutic strategy for HF treatment. However, assessing the therapeutic potential of m preservation is challenging, due to a lack of tools for dynamic and specific control of CM m in live animals. To overcome this technical barrier, we developed an innovative mitochondrial-targeted luminoptogenetic (named mLumOpto) technology by integrating luciferase- luciferin-emitted endogenous bioluminescence with the mitochondrial optogenetics we recently published. Our preliminary data indicate that mLumOpto can induce dynamic CM m control in the absence of external light illumination. The primary goal of this project is to employ this advanced mLumOpto technology to manipulate CM m in vivo to evaluate the efficacy of CM m preservation alone, or in synergism with a mtROS scavenger (i.e., mitochondrial-specific antioxidant), in HF treatment in preclinical mouse models. The translational potential of the proposed synergistic mitochondrial-targeted HF therapy will also be assessed in human-like large animals (i.e., pigs). Three Specific Aims are proposed to accomplish our objectives. Aim 1 will determine the role of sustained CM m depolarization in pathological cardiac remodeling and HF development in mice, and dissect the underlying molecular mechanisms. Aim 2 will evaluate the efficacy of synergistic m preservation and mtROS scavenging in improving adverse cardiac remodeling and contractile dysfunction in two well-established mouse HF models (i.e., pressure overload and myocardial ischemia-reperfusion). Aim 3 will assess the translational potential of mLumOpto-mediated HF therapy in pigs. Successful completion of this project will lead to not only an innovative technology capable of specifically and dynamically manipulating CM mitochondria in vivo, but also a novel translational mitochondrial-targeted therapy for HF treatment.

摘要/摘要心力衰竭 (HF) 是世界范围内死亡的主要原因，尽管 HF 的病理生理学非常复杂。仍不完全清楚，线粒体功能缺陷与进展有关心力衰竭的结果，并成为心力衰竭治疗的一个众所周知的影响因素。衰竭心脏中的不良心脏重塑是线粒体衍生的活性氧过多 (mtROS)，多年来已经开发出多种基于抗氧化剂的疗法用于心力衰竭治疗。然而，尽管临床前研究取得了有希望的成果，但这些疗法仍无法转化为实际应用。迄今为止，诊所尚未取得成功，这表明替代或补充的线粒体治疗靶点除了过量的 mtROS 之外，线粒体膜电位 (m) 的严重丧失也是需要的。在心肌细胞 (CM) 中，m 破坏不仅影响能量产生，还影响心肌细胞的能量产生。对细胞功能和生存至关重要的多种信号通路，例如氧化还原平衡、钙稳态和线粒体质量控制，我们突袭了协同靶向线粒体，即同时进行。保留线粒体m并清除多余的mtROS，是治疗心力衰竭的可行治疗策略。然而，由于缺乏工具，评估 m 保存的治疗潜力具有挑战性。为了克服这一技术障碍，我们开发了一种对活体动物中 CM m 进行动态和特异性控制的方法。通过整合荧光素酶的创新线粒体靶向发光（名为mLumOpto）技术我们最近发表了利用线粒体光遗传学研究荧光素发射的内源生物发光的方法。初步数据表明mLumOpto可以在没有外部光的情况下诱导动态CM m控制该项目的主要目标是采用这种先进的 mLumOpto 技术来操纵。 CM m 体内评估单独保存 CM m 或与 mtROS 清除剂协同作用的功效（即线粒体特异性抗氧化剂）在临床前小鼠模型的 HF 治疗中的转化潜力。拟议的协同线粒体靶向心力衰竭治疗的效果也将在类人大型动物中进行评估（即猪）。为实现我们的目标提出了三个具体目标，其中目标 1 将确定其作用。小鼠病理性心脏重塑和心力衰竭发展中持续的 CM m 去极化，并解剖目标 2 将评估 m 保存和协同作用的功效。 mtROS 清除可改善两种成熟的不良心脏重塑和收缩功能障碍小鼠心力衰竭模型（即压力超负荷和心肌缺血再灌注）将评估。 mLumOpto 介导的 HF 疗法在猪中的转化潜力将引领该项目的成功完成。不仅是一种能够特异性、动态地操纵 CM 线粒体的创新技术体内，也是一种用于心力衰竭治疗的新型转化线粒体靶向疗法。