RNA Toxicity and Cardiac Pathology

RNA 毒性和心脏病理学

• 批准号: 10705364
• 负责人: Mani Subramaniam Mahadevan
• 金额: $ 75.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705364
• 关键词: Adult; Affect; Antibodies; Antisense Oligonucleotides; Arrhythmia; Attention; Behavior; Biological Assay; Biological Markers; Cardiac; Cardiac conduction system; Cause of Death; Cells; Child; Clinical; Clinical Pathology; Clinical Trials; Collaborations; Data; Defect; Degenerative Disorder; Deposition; Development; Disease Progression; Dominant Genetic Conditions; Electrocardiogram; Evaluation; Fatty acid glycerol esters; Fibrosis; Frequencies; Genes; Genetic Diseases; Goals; Heart; Heart Abnormalities; Heart Diseases; Histologic; Individual; Infiltration; Magnetic Resonance Imaging; Molecular; Monitor; Mus; Muscular Dystrophies; Myotonic Dystrophy; Myotonic dystrophy type 1; Nuclear; Organ; Outcome Measure; PDGFRA gene; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Pirfenidone; Pre-Clinical Model; Production; Protein Isoforms; Protocols documentation; Published Comment; RNA; Reporter; Reporting; Research; Research Personnel; Role; Signal Transduction; Standardization; Sudden Death; Symptoms; System; Therapeutic Studies; Therapeutic Trials; Time; Tissues; Toxic effect; Transforming Growth Factor beta; antifibrotic treatment; base; cardiac magnetic resonance imaging; coronary fibrosis; heart function; interest; interstitial; mouse model; mutant; myotonic dystrophy protein kinase; next generation; preclinical study; response; targeted treatment; tool; treatment response

Project Summary: Myotonic dystrophy (DM1), the most common form of muscular dystrophy in adults and children, is an autosomal dominant genetic disorder caused by an expanded CTG repeat in the DM protein kinase (DMPK) gene that leads to nuclear retention of the mutant RNA and subsequent RNA toxicity. The heart is one of the primary organs affected in DM1. Cardiac conduction problems are present in up to 75% of adult DM1 cases, and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is not well understood. Clinical focus for cardiac disease in DM1 has been on arrhythmias and conduction abnormalities. Of note, the pathology of cardiac defects in DM1 has been historically associated with interstitial fibrosis, and fatty infiltration and fibrosis of cardiac conduction tissues. We reported the first inducible mouse model of RNA toxicity and cardiac conduction defects and demonstrated the potential for reversibility of DM1 phenotypes by silencing toxic RNA production. Recently using the DM200 mouse model, we showed for the first time, the potential for antisense oligonucleotides (ASOs) to treat cardiac disease in DM1. We also found evidence for fibrotic changes associated with RNA toxicity in the heart. In the past decade, the advent of new cardiac MRI studies has led to evidence of and an increased interest in understanding cardiac fibrosis in DM1 and its role in the clinical pathology of DM1. We propose to use the DM200 mouse model as a tool for developing and investigating these ideas and concepts in a pre-clinical model and to try to understand the cellular and molecular drivers of fibro-adipogenic changes in the heart. We will do this through three independent but complementary aims. First, we will develop and evaluate cardiac MRI as a biomarker for RNA toxicity in the heart. Second, we will determine the role of cardiac PDGFRA+ve cells in fibro/adipogenic pathologic responses to RNA toxicity in the heart. Third, based on preliminary evidence of increased TGFβ in the heart, we will characterize the role of TGFβs in RNA toxicity in the heart, and study the therapeutic response to therapies targeting fibrosis and TGFβ (including isoform specific antibodies against TGFβ2 and TGFβ3). Importantly, we will validate the CMR protocols and parameters in therapeutic trials using: a) next generation ASOs that target the toxic RNA and b) the therapies targeting fibrosis and TGFβs. Our goals are to understand the drivers of cardiac pathology associated with RNA toxicity in DM1, and to evaluate and establish the potential utility of cardiac MRI as a tool to monitor disease progression and response to therapy.

项目摘要： 肌营养不良症（DM1）是成​​人和儿童最常见的肌肉营养不良的形式，是一种常染色体 由DM蛋白激酶（DMPK）基因扩展的CTG重复膨胀引起的主要遗传疾病 突变体RNA的核保留及随后的RNA毒性。心脏是主要器官之一 在DM1中受到影响。心脏传导问题最多有75％的成人DM1病例和猝死 由于心脏心律不齐是DM1中最常见的死亡原因之一。不幸的是，发病机理 DM1中的心脏表现尚不清楚。 DM1中心脏病的临床重点一直在 心律不齐和传导异常。值得注意的是，DM1中心脏缺陷的病理一直是历史上的 与心脏传导组织的脂肪纤维化以及脂肪浸润和纤维化有关。我们报道 RNA毒性和心脏传导缺陷的第一个诱导小鼠模型，并证明了潜力 通过沉默有毒的RNA产生，DM1表型的可逆性。最近使用DM200鼠标模型， 我们首次展示了反义寡核苷酸（ASO）在DM1中治疗心脏病的潜力。 我们还发现了与心脏RNA毒性相关的纤维化变化的证据。在过去的十年中， 新的心脏MRI研究的出现导致了对理解心脏的证据并增加了兴趣 DM1中的纤维化及其在DM1临床病理中的作用。我们建议将DM200鼠标模型用作 用于在临床前模型中开发和研究这些思想和概念的工具，并试图理解 心脏纤维辅助变化的细胞和分子驱动因素。我们将通过三个 独立但完全的目标。首先，我们将开发和评估心脏MRI作为RNA的生物标志物 心脏的毒性。其次，我们将确定心脏PDGFRA+VE细胞在纤维/脂肪生成中的作用 对心脏RNA毒性的病理反应。第三，基于TGFβ中增加的初步证据 心脏，我们将表征TGFβ在心脏中RNA毒性中的作用，并研究治疗反应 靶向纤维化和TGFβ的疗法（包括针对TGFβ2和TGFβ3的同工型特异性抗体）。 重要的是，我们将在热试验中验证CMR方案和参数：a）下一代 靶向有毒RNA和b）靶向纤维化和TGFβ的疗法的ASO。我们的目标是了解 与DM1中RNA毒性相关的心脏病理驱动因素，并评估和确定潜力 心脏MRI作为监测疾病进展和对治疗反应的工具。