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.

项目概要： 强直性肌营养不良 (DM1) 是成人和儿童最常见的肌营养不良症，是一种常染色体遗传性肌营养不良症 由 DM 蛋白激酶 (DMPK) 基因中扩大的 CTG 显性重复序列引起的遗传性疾病，该基因导致 心脏是主要器官之一。 高达 75% 的成人 DM1 病例存在心脏传导问题，并导致猝死。 因心律失常是DM1最常见的死亡原因之一，但其发病机制却很不幸。 DM1 患者的心脏表现尚不清楚，临床焦点一直集中在 DM1 患者的心脏疾病上。 心律失常和传导异常 值得注意的是，DM1 心脏缺陷的病理学在历史上一直存在。 我们报道了与间质纤维化以及心脏传导组织的脂肪浸润和纤维化有关。 第一个诱导 RNA 毒性和心脏传导缺陷的小鼠模型，并证明了其潜力 最近使用 DM200 小鼠模型，通过沉默有毒 RNA 的产生来实现 DM1 表型的可逆性。 我们首次展示了反义寡核苷酸 (ASO) 治疗 DM1 型心脏病的潜力。 我们还发现了与心脏中 RNA 毒性相关的纤维化变化的证据。 新的心脏 MRI 研究的出现带来了了解心脏的证据并增加了人们的兴趣 DM1 中的纤维化及其在 DM1 临床病理学中的作用我们建议使用 DM200 小鼠模型作为模型。 用于在临床前模型中开发和研究这些想法和概念并尝试理解的工具 我们将通过三个方面来研究心脏纤维脂肪生成变化的细胞和分子驱动因素。 首先，我们将开发和评估心脏 MRI 作为 RNA 生物标志物。 其次，我们将确定心脏 PDGFRA+ve 细胞在纤维/脂肪形成中的作用。 第三，基于心脏中 TGFβ 增加的初步证据。 心脏，我们将表征 TGFβ 在心脏 RNA 毒性中的作用，并研究治疗反应 针对纤维化和 TGFβ 的治疗（包括针对 TGFβ2 和 TGFβ3 的异构体特异性抗体）。 重要的是，我们将使用以下方式验证治疗试验中的 CMR 方案和参数：a) 下一代 针对有毒 RNA 的 ASO 和 b) 针对纤维化和 TGFβ 的疗法我们的目标是了解。 与 DM1 中 RNA 毒性相关的心脏病理学驱动因素，并评估和确定潜在的 心脏 MRI 作为监测疾病进展和治疗反应的工具的效用。