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.

项目概要 杜氏肌营养不良症 (DMD) 的特点是膜不稳定、钙内流和肌营养不良 在心脏中，心肌细胞的逐渐分解导致纤维化和隐匿性扩张。 心肌病是 DMD 患者死亡的主要原因。 尽管有传统的心脏支持疗法，但我们的初步研究表明，信号传导仍然存在。 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，预防这种活动可以保护肌营养不良症患者的心脏功能。 研究小组发现，用拮抗剂伊非曲班阻断 TPr 活性可改善生存、心脏功能和 两种严重 DMD 小鼠模型和肢带型肌营养不良症模型中的心脏纤维化。 这些研究是伊非曲班治疗 DMD 患者的 2 期临床研究，目前正在招募中。 我们知道，TPr 激活会导致肿瘤生长因子 (TGF) 增强的纤维化。 β 活性，但不是它如何激活 TGFβ 在这里，我们将检验 Tpr 激活介导 TGF-β 的假设。 从大的潜在复合物中释放，导致心脏纤维化，我们将在 TPR 的背景下测试这一点。 使用 mdx/utrn(+/-) 小鼠或含有潜在 TGF-β 结合蛋白 4 (LTBP4) 的 mdx 小鼠进行阻断或缺失 多态性，并用分离的成纤维细胞进行证实，我们的早期数据也表明了其机制。 Tpr调节心肌细胞膜稳定性，心律失常和心脏功能可能与此不同。 我们认为这是通过调节钙流入和钙激活信号发生的，并且 拮抗作用以与标准治疗 DMD 相加的方式改善 mdx/utrn(+/-) 小鼠的这种情况。 含有心肌细胞特异性删除 TPr 的小鼠模型将把心肌细胞起始的与 最后，我们正在进行的试验提供了评估分子结果的独特机会。 在人类患者中进行纵向研究，并确定生物标志物来反映心脏对 Tpr 拮抗剂的反应。 为了实现这一目标，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的比较 解决这些问题将阐明这一点。 Tpr 在 DMD 心肌病中的作用、预测人类反应以及 Tpr 拮抗机制 DMD 患者，可以为药物反应提供有价值的替代终点。