Activity and therapeutic antagonism of the TP receptor in cardiomyopathy of muscular dystrophy

TP受体在肌营养不良性心肌病中的活性和治疗拮抗作用

• 批准号: 10736005
• 负责人: JAMES D WEST
• 金额: $ 70.22万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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/10736005
• 关键词: Address; Affect; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Arrhythmia; Binding Proteins; Biological Markers; Calcium; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiomyopathies; Cause of Death; Cell Membrane Permeability; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Complex; Coupled; Data; Deterioration; Diffuse; Dilated Cardiomyopathy; Dose; Duchenne cardiomyopathy; Duchenne muscular dystrophy; Dystrophin; Enrollment; Expression Profiling; Fibroblasts; Fibrosis; GTP-Binding Proteins; Generations; Genes; Genetic Polymorphism; Goals; Heart; Heart failure; Human; Immune; Individual; Isoproterenol; Knockout Mice; Knowledge; Life; Limb-Girdle Muscular Dystrophies; Magnetic Resonance; Mediating; Membrane; Messenger RNA; Modeling; Molecular; Mus; Muscle Cells; Muscular Atrophy; Muscular Dystrophies; Muscular dystrophy cardiomyopathy; Mutation; Myocardial dysfunction; Necrosis; Newborn Infant; Oral; Outcome; Participant; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Phenotype; Physiologic intraventricular pressure; Play; Predisposition; Prednisone; Prevention; Prostaglandins; Proteins; Receptor Activation; Regulation; Renin; Research; Role; Signal Transduction; Smooth Muscle; Stress; Surrogate Endpoint; Telomere Shortening; Testing; Therapeutic; Thromboxane Receptor; Thromboxanes; Transforming Growth Factor beta; Transforming Growth Factors; Utrophin; Water; Weaning; antagonist; biomarker identification; boys; coronary fibrosis; drinking water; driving force; heart function; heart preservation; ifetroban; improved; induced pluripotent stem cell derived cardiomyocytes; inhibitor; male; mdx mouse; mouse model; muscular dystrophy mouse model; premature; prevent; receptor; recruit; response; standard of care; success; transcriptomic profiling; treatment group; treatment response

PROJECT SUMMARY Duchenne muscular dystrophy (DMD) is characterized by membrane instability, calcium influx, and necrosis of myocytes. In the heart, progressive breakdown of cardiomyocytes causes fibrosis and an insidious dilated cardiomyopathy. Heart failure is the primary cause of death in patients with DMD, which occurs around the third decade despite traditional cardiosupportive therapeutics. Our preliminary research suggests that signaling from the thromboxane-prostanoid receptor (TPr) in the heart is a driving force leading to cardiomyocyte death and fibrosis, and preventing this activity may preserve cardiac function in muscular dystrophy patients. Our group has found that blocking TPr activity with the antagonist ifetroban improves survival, cardiac function, and cardiac fibrosis in two mouse models of severe DMD and a model of limb-girdle muscular dystrophy. Based on these studies, a Phase 2 clinical study of ifetroban in DMD patients is currently recruiting. However, key knowledge gaps exist. We know that TPr activation leads to fibrosis with enhanced tumor growth factor (TGF)- β activity, but not how it activates TGFβ. Here we will test the hypothesis that TPr activation mediates TGF-β release from the large latent complex, leading to cardiac fibrosis. We will test this in the context of TPr blockade or deletion, using mdx/utrn(+/-) mice or mdx mice containing latent TGF-β binding protein-4 (LTBP4) polymorphism, and confirm with isolated fibroblasts. Our early data also suggests that the mechanism by which TPr regulates cardiomyocyte membrane stability, arrhythmia, and cardiac function may be distinct from this. We hypothesize this occurs via regulation of calcium influx and calcium-activated signaling, and that antagonism improves this in mdx/utrn(+/-) mice in a manner additive with standard-of-care therapies. A DMD mouse model containing a cardiomyocyte-specific deletion of TPr will separate cardiomyocyte-initiated from fibroblast effects. Finally, our ongoing trial presents a unique opportunity to assess molecular outcomes longitudinally in human patients, and identify biomarkers to reflect the cardiac response to TPr antagonism. For this aim, we will do expression profiling of peripheral blood mononuclear cells from DMD patient participants in the ifetroban clinical trial, compared with response to treatment. Resolving these questions will illuminate the role of the TPr in DMD cardiomyopathy, anticipate human response and mechanism of TPr antagonism in DMD patients, and could provide valuable surrogate endpoints for drug response.

项目总结 Duchenne肌营养不良症(DMD)的特征是膜不稳定、钙内流和坏死。 肌细胞。在心脏，心肌细胞的进行性分解会导致纤维化和潜伏的扩张。 心肌病。心力衰竭是DMD患者死亡的主要原因，发生在 第三个十年，尽管有传统的心脏支持疗法。我们的初步研究表明，信号 心脏中的血栓素前列腺素受体(TPR)是导致心肌细胞死亡的驱动力 和纤维化，而阻止这种活动可能会保护肌营养不良患者的心功能。我们的 研究小组发现，用拮抗剂伊非罗班阻断TPR活性可提高存活率、心功能和 两种严重DMD小鼠模型和一种四肢带状肌营养不良模型中的心脏纤维化。基于 这些研究是伊非曲班在DMD患者中的第二阶段临床研究，目前正在招募中。但是，关键字 知识差距是存在的。我们知道，TPR的激活会导致纤维化，并伴随着增强的肿瘤生长因子(TGF)- β活性，但不是它如何激活转化生长因子β。在这里，我们将检验TPR激活介导转化生长因子-β的假设 从大的潜伏复合体中释放，导致心脏纤维化。我们将在TPR的背景下测试这一点 阻断或删除，使用mdx/UTUN(+/-)小鼠或含有潜伏的转化生长因子-β结合蛋白-4的mdx小鼠 多态，并与分离的成纤维细胞证实。我们早期的数据还表明， TPR调节心肌细胞膜稳定性、心律失常，心功能可能与此不同。 我们假设这是通过调节钙内流和钙激活信号发生的，并且 拮抗以一种附加标准护理疗法的方式改善MDX/UTUN(+/-)小鼠的这种情况。一个DMD 含有心肌细胞特异性TPR缺失的小鼠模型将从心肌细胞启动的 成纤维细胞效应。最后，我们正在进行的试验提供了一个独特的机会来评估分子结果 在人类患者中进行纵向研究，并确定反映心脏对TPR拮抗反应的生物标志物。为 为此，我们将对DMD患者参与者的外周血单核细胞进行表达谱分析 伊非曲班临床试验，与治疗反应进行比较。解决这些问题将照亮 TPR在DMD心肌病中的作用、预测人的反应及TPR拮抗DMD的机制 DMD患者，并可为药物反应提供有价值的替代终点。