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）是全球死亡的主要原因。尽管HF的病理生理学很复杂，并且仍然不完全理解，在进展中隐含了线粒体功能的缺陷 HF的结果，成为HF治疗的重要靶标。一个众所周知的贡献因素失败心脏中的不良心脏重塑超过线粒体衍生的活性氧（mtros）。彼此之间，已经开发了各种基于抗氧化剂的疗法最近几十年。然而，尽管临床前研究有希望的结果，但这些疗法将其转化为诊所迄今尚未成功，这表明替代或完整的线粒体治疗靶标需要。除了超过MTRO，线粒体膜电位（M）的深刻损失是另一种 HF的关键标志。在心肌细胞（CM）中，M不仅会影响能量产生，还会影响多种信号通路对细胞功能和生存至关重要，例如氧化还原平衡，钙稳态和线粒体质量控制。我们假设协同靶向线粒体，即同时靶向保持线粒体M和清除超过MTROS，是HF治疗的可行治疗策略。但是，由于缺乏工具，评估M保存的治疗潜力是具有挑战性的活动物中CMM的动态和特定控制。为了克服这一技术障碍，我们开发了通过整合荧光素酶 - 我们最近发表的线粒体光遗传学的荧光素发射的内源性生物发光。我们的初步数据表明Mlumopto可以在没有外部光线的情况下诱导动态CMM控制照明。该项目的主要目的是利用这种先进的Mlumopto技术来操纵 cmM体内评估单独保存CM的效率，或与MTROS清除剂的协同作用（即线粒体特异性抗氧化剂），在临床前小鼠模型中的HF处理中。翻译的潜力在拟议的协同线粒体靶向的HF疗法中，还将在类似人类的大型动物中进行评估（即猪）。提出了三个具体目标来实现我们的目标。 AIM 1将决定病理心脏重塑和小鼠HF发育中持续的商业M沉积，并剖析潜在的分子机制。 AIM 2将评估协同M保存的效率和 Mtros清除了两个公认的不良心脏重塑和收缩功能障碍小鼠HF模型（即压力超负荷和心肌缺血再灌注）。 AIM 3将评估 Mlumopto介导的HF疗法在猪中的转化潜力。成功完成该项目将领导不仅能够专门和动态地操纵CM线粒体的创新技术体内，也是一种新型的翻译线粒体靶向HF治疗的疗法。