Parkin activators for cardioprotective therapies

用于心脏保护治疗的 Parkin 激活剂

基本信息

批准号：
10382817
负责人：
Kumar Suresh
金额：
$ 29.69万
依托单位：
PROGENRA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382817
关键词：
Adult Agonist Animal Model Attenuated Autophagocytosis Binding Biogenesis Biological Assay Cardiac Cardiac Myocytes Cell model Cells Cervix carcinoma Clinical Trials Coronary artery Cytosol Data Development EFRAC Excision Fibroblasts Fibrosis Fluorescence Resonance Energy Transfer Goals Heart Heart failure High Fat Diet Hyperactivity Impairment In Vitro Infarction Infiltration Inflammation Inflammatory Injections Intervention Kidney Knockout Mice Left Ventricular Remodeling Ligation Link Mediating Mitochondria Mitochondrial Proteins Molecular Mus Myocardial Infarction Natural Immunity Neuroblastoma Obese Mice PINK1 gene Parkin Pathologic Pathway interactions Patients Pattern Performance Pharmaceutical Preparations Phase Phosphotransferases Process Production Quality Control Rattus Reactive Oxygen Species Reperfusion Injury Respiratory physiology Rodent Model Role Safety Signal Transduction Site Specificity Stimulation of Cell Proliferation Therapeutic Therapeutic Agents Thinness Ubiquitination Variant Wild Type Mouse base cardioprotection clinically relevant cytotoxicity diet-induced obesity effective therapy heart function high throughput screening improved in vivo mitochondrial dysfunction mouse model new therapeutic target novel novel therapeutics overexpression porcine model preclinical development prevent sham surgery small molecule small molecule libraries ubiquitin ligase ubiquitin-protein ligase

项目摘要

Myocardial infarction followed by left ventricular remodeling is the leading cause of heart failure (HF). Current therapies are inadequate to modulate adverse remodeling and prevent subsequent cardiac failures. As such there is a critical unmet need to identify new therapies. There is strong evidence suggesting that mitophagy exerts cardioprotective effects following infarction (MI) and that impaired mitochondrial biogenesis contributes to HF. Mitochondrial dysfunction reduces energy production, releasing harmful reactive oxygen species and proinflammatory molecules, which contribute to the ischemic reperfusion injury leading to HF. Regulated and selective clearance of damaged mitochondria via mitophagy orchestrated by PINK1 kinase and Parkin ubiquitin ligase, is a key mitochondrial quality control mechanism. Moreover, Parkin has been shown to regulate mitogenesis by ubiquitinating and degrading PARIS, a key repressor of PGC1, the positive regulator of mitogenesis. For these reasons, intervention to promote the Parkin-mediated mitochondrial quality control pathway is a promising therapeutic strategy to prevent or ameliorate post-MI heart failure. Parkin exists in an auto-inhibited state in cells and is activated by PINK1. Progenra utilized a novel TR-FRET assay and discovered small molecules that bind and activate Parkin selectively. Consistent with Parkin activation, these Parkin activator compounds (PACs) degrade Parkin substrates (e.g. PARIS) and potently upregulate mitophagy in various cell models. In addition, PACs promoted mitochondrial turnover in Mitotimer mice after permanent coronary artery ligation (PCAL). Most important, administration of PAC (1mg/kg) in mice after PCAL resulted in profound mitigation of adverse cardiac remodeling and fibrosis leading to improved cardiac function and survival of wild type mice after PCAL. Thus, we have established preliminary in vivo proof of cardioprotection by PAC. In this phase I proposal, we will use adult rat primary cardiomyocytes as well as clinically relevant diet-induced obesity mouse model subjected to PCAL to further evaluate and characterize the cardioprotective role of PACs. Improvements in cardiac performance, survival, fibrosis, mitochondrial composition and function, and the landscape of Parkin-mediated ubiquitylome will be determined. In Phase II, we will evaluate long-term safety and efficacy of PACs in rodent and swine models, particularly their ability to improve cardiac functions post-MI, attenuate adverse remodeling, and suppress inflammation and fibrosis driven by innate immunity. The ultimate goal is the development of Parkin activator that can be used to treat post-MI reperfusion injury and prevent heart failure.

心肌梗塞继发的左心室重构是心力衰竭（HF）的主要原因。目前的疗法不足以调节不良重塑并预防随后的心力衰竭。因此，存在确定新疗法的关键未满足的需求，有强有力的证据表明线粒体自噬。在梗塞 (MI) 后发挥心脏保护作用，线粒体生物合成受损会导致线粒体功能障碍会减少能量产生，释放有害的活性氧和促炎分子，导致缺血性再灌注损伤，导致心力衰竭。通过 PINK1 激酶和 Parkin 泛素协调的线粒体自噬选择性清除受损线粒体连接酶是一种关键的线粒体质量控制机制，并且 Parkin 已被证明具有调节作用。通过泛素化和降解 PARIS 来促进有丝分裂，PARIS 是 PGC1 的关键抑制因子，PGC1 是有丝分裂的正调节因子由于这些原因，干预可促进 Parkin 介导的线粒体质量控制。 Parkin 通路是预防或改善 MI 后心力衰竭的一种有前途的治疗策略。 Progenra 利用一种新型 TR-FRET 测定发现了细胞中的自身抑制状态，并被 PINK1 激活。选择性结合并激活 Parkin 的小分子，与 Parkin 激活一致，这些 Parkin 激活剂。化合物 (PAC) 降解 Parkin 底物（例如 PARIS）并有效上调各种细胞中的线粒体自噬此外，PACs 还能促进 Mitotimer 小鼠永久性冠状动脉粥样硬化后的线粒体更新。最重要的是，在 PCAL 后给小鼠施用 PAC (1mg/kg) 会产生深远的影响。减轻不利的心脏重塑和纤维化，从而改善心脏功能和野生动物的生存因此，我们已经建立了 PAC 心脏保护作用的初步体内证据。第一阶段提案，我们将使用成年大鼠原代心肌细胞以及临床相关的饮食诱导肥胖对小鼠模型进行 PCAL，以进一步评估和表征 PAC 的心脏保护作用。改善心脏性能、存活率、纤维化、线粒体组成和功能以及 Parkin 介导的泛素组的前景将在第二阶段确定，我们将评估长期安全性和稳定性。 PAC 在啮齿动物和猪模型中的功效，特别是其改善 MI 后心脏功能的能力，减轻不良重塑，抑制先天免疫驱动的炎症和纤维化。目标是开发可用于治疗心肌梗死后再灌注损伤并预防心脏病的 Parkin 激活剂失败。