The role of TGFβs and cFAPs in Cardiac Pathology from RNA Toxicity

TGFβ 和 cFAP 在 RNA 毒性心脏病理学中的作用

• 批准号: 10717904
• 负责人: Mani Subramaniam Mahadevan
• 金额: $ 80.7万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717904
• 关键词: Ablation; Adult; Affect; Alleles; Antibodies; Antisense Oligonucleotides; Arrhythmia; Attention; Behavior; Biological Assay; Biological Markers; Breeding; Cardiac; Cardiac Myocytes; Cause of Death; Child; Clinical; Clinical Pathology; Clinical Research; Collaborations; Data; Defect; Degenerative Disorder; Development; Dominant Genetic Conditions; Dose; Doxycycline; Electrocardiogram; Fatty Acids; Fibrosis; Future; Gene Deletion; Gene Expression; Genes; Genetic Diseases; Goals; Grant; Heart; Heart Abnormalities; Heart Diseases; Histology; Individual; Infiltration; Ligands; Lipid Inclusion; LoxP-flanked allele; Maintenance; Mediating; Molecular; Morbidity - disease rate; Mus; Muscle; Muscular Dystrophies; Myotonic Dystrophy; Myotonic dystrophy type 1; Nature; Nuclear; Organ; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Platelet-Derived Growth Factor alpha Receptor; Pre-Clinical Model; Production; Proliferating; Protein Isoforms; RNA; Reporting; Role; Signal Transduction; Stains; Sudden Death; Symptoms; System; Tamoxifen; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Time; Tissues; Toxic effect; Transforming Growth Factor Beta 2; Transforming Growth Factor beta; Transgenes; autosome; behavioral study; cardiac magnetic resonance imaging; coronary fibrosis; functional outcomes; inducible Cre; insight; interest; interstitial; mortality; mouse model; mutant; myotonic dystrophy protein kinase; next generation; novel; progenitor; receptor; response; stem cells; targeted treatment; therapeutic target; 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 (CMR) 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 four independent but complementary aims. First, based on preliminary evidence of increased TGFβs expression in the heart, we will determine the role of TGFβs from cardiomyocytes, in RNA toxicity in the heart. Second, we will study the behavior of cardiac fibro-adipogenic progenitors (cFAP) cells and the role of TGFβ signaling in cFAPs in pathologic responses to RNA toxicity. Third, we will study the therapeutic response to therapies targeting TGFβs (isoform specific antibodies against TGFβ2 and TGFβ3). Fourth, we will evaluate next generation ASOs that target the toxic RNA. With both these classes of therapy, we will assess their therapeutic effect on fibroadipogenic changes, cFAPs, TGFβ expression and cardiac outcomes, by using ECGs and CMR and functional testing. The ultimate goal of this proposal is to elucidate critical players in the primary pathologies associated with RNA toxicity in the heart, and to identify pathways and therapies that may mitigate morbidity and mortality associated with cardiac disease in DM1.

项目总结： 强直性肌营养不良症(DM1)是成人和儿童中最常见的肌营养不良症，是一种常染色体 由糖尿病蛋白激酶(DMPK)基因扩大的CTG重复导致的显性遗传疾病 与突变RNA的核滞留和随后的RNA毒性有关。心脏是人体的主要器官之一 在DM1中受影响。高达75%的成年DM1患者存在心脏传导问题，猝死 由于心律失常是DM1最常见的死亡原因之一。不幸的是，其发病机制 DM1的心脏表现还不是很清楚。DM1中心脏病的临床焦点一直在 心律失常和传导异常。值得注意的是，dm1中心脏缺陷的病理已经有了历史。 与间质纤维化、心脏传导组织脂肪渗出和纤维化有关。我们报道了 第一个可诱导的小鼠RNA毒性和心脏传导缺陷模型，并展示了其潜在的 通过沉默有毒RNA的产生，使DM1表型可逆性。最近使用的是DM200鼠标模型， 我们首次在DM1中展示了反义寡核苷酸(ASO)治疗心脏病的潜力。 我们还发现了与心脏中RNA毒性相关的纤维化改变的证据。在过去的十年里， 新的心脏磁共振(CMR)研究的出现导致了对理解的证据和兴趣的增加 DM1心肌纤维化及其在DM1临床病理中的作用。我们建议使用DM200小鼠模型 作为在临床前模型中开发和研究这些想法和概念的工具，并尝试 了解心脏纤维成脂变化的细胞和分子驱动因素。我们会把这件事做完 四个独立但相辅相成的目标。首先，基于转化生长因子βS表达增加的初步证据 在心脏方面，我们将确定转化生长因子βS在心肌细胞核糖核酸在心脏毒性中的作用。第二，我们 将研究心脏纤维脂肪前体细胞的行为和转化生长因子β信号转导在 CFAP在RNA毒性的病理反应中的作用。第三，我们将研究治疗的疗效。 靶向转化生长因子βS(抗转化生长因子β2和转化生长因子β3的异构体特异性抗体)。第四，我们接下来将进行评估 产生以有毒RNA为靶标的ASO。对于这两种疗法，我们将评估它们的治疗效果 心电地形图和心磁共振仪对成纤维细胞变化、cFAP、转化生长因子β表达和心脏结局的影响 和功能测试。这项建议的最终目的是阐明主要病理中的关键因素。 与心脏中的RNA毒性有关，并确定可能减少发病率和 DM1中与心脏病相关的死亡率。