Paracrine actions of fibroblasts promote pathologic cardiac myocyte remodeling in Duchenne muscular dystrophy

成纤维细胞的旁分泌作用促进杜氏肌营养不良症的病理性心肌细胞重塑

基本信息

批准号：
10276418
负责人：
Steven S Welc
金额：
$ 52.54万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10276418
关键词：
Acute Affect Attenuated Binding Calcineurin Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cell Culture Techniques Cells Cessation of life Cicatrix Cleaved cell Clinical Coculture Techniques Complex Data Defect Development Disease Disease Progression Duchenne cardiomyopathy Duchenne muscular dystrophy Dystrophin Event Extracellular Domain Extracellular Matrix FGFR4 gene Fibroblast Growth Factor Receptors Fibroblasts Fibrosis General Population Genes Genetic Goals Heart Heart Diseases Hormones Hypertrophy Image Impairment Inflammation Injury Investigation Kidney Kidney Diseases Knock-in Knowledge Life Expectancy Longevity Mechanics Mediating Mission Morbidity - disease rate Muscle Muscle Cells Muscular Atrophy Mutation Myocardium Myopathy National Heart, Lung, and Blood Institute Onset of illness Outcome Pathogenicity Pathologic Pathology Patients Phospholipase Production Public Health Research Research Personnel Respiratory Insufficiency Signal Transduction Skeletal Muscle System Testing Therapeutic Ventricular Dysfunction Work cardioprotection cellular targeting disease-causing mutation dystrophic cardiomyopathy experimental study fibroblast growth factor 23 fibroblast growth factor receptor 4 functional disability gain of function genetic approach heart function heart preservation improved innovation inorganic phosphate loss of function mdx mouse mortality mouse model new therapeutic target novel nuclear factors of activated T-cells paracrine receptor targeted treatment therapeutic target transgene expression

项目摘要

PROJECT SUMMARY: The long-term goal of our research is to improve our understanding of the pathologic mechanisms of Duchenne muscular dystrophy (DMD) and to leverage that knowledge to advance therapeutics. Progress in treating respiratory insufficiency and other complications of muscle deterioration has led to cardiac disease emerging as a principal cause of morbidity and mortality in DMD. Consequently, there is a critical need to identify the specific pathogenic mechanisms that promote DMD-related cardiac disease so that targeted therapeutics can be developed. The complex pathology initiates with mechanically compromised myocytes but is intertwined with secondary defects that contribute importantly to disease progression. Fibrosis is one of the earliest clinical manifestations of cardiac involvement in DMD occurring prior to ventricular dysfunction indicating the presence of activated fibroblasts early in the progression of pathology. Fibroblasts produce extracellular matrix that comprises fibrotic scar, but it is not known whether they possess other maladaptive functions that affect disease progression. Our preliminary findings now show that fibroblast growth factor (FGF) 23 is greatly increased in cardiac fibroblasts of mdx mice, a genetic mouse model of DMD. Elevated FGF23 is remarkably associated with important clinical events related to cardiovascular disease and mortality in patients with renal disease and in the general population. FGF23 is a hormone that mostly works in cooperation with its co-receptor Klotho, but can also stimulate pathological signaling in atypical cellular targets. FGF23 exerts pathologic effects on cardiac myocytes by binding to FGF receptor (FGFR) 4 independent of Klotho, which is not expressed in the heart. Our central hypothesis is that dystrophic cardiac fibroblasts exert paracrine effects on cardiac myocytes via FGF23, thereby activating FGFR4 to promote cardiac disease in DMD. Our preliminary findings showing that Klotho is cardioprotective in mdx mice strongly supports our hypothesis that FGF23 signaling contributes importantly to cardiac remodeling. The central hypothesis will be tested by pursuing two comprehensive specific aims. In Aim 1 we will test whether FGF23 is a paracrine factor produced by cardiac fibroblasts that promotes dystrophin-deficient cardiac pathology and functional defects using a conditional genetic approach combined with ex vivo cell culture experiments. In Aim 2 we will determine whether FGFR4 activation in cardiac myocytes affects dystrophin-deficient cardiac remodeling and function using complementary loss-of-function and gain-of- function genetic approaches. The proposed research is innovative because it is predicted to show that fibroblasts exert regulatory effects on cardiac myocytes and establish FGF23/FGFR4 signaling as a novel pathogenic mechanism of DMD. This contribution is significant because it is expected to provide strong mechanistic justification for modulating FGF23/FGFR4 as a therapeutic target to treat DMD.

项目摘要：我们研究的长期目标是提高我们对病理学的理解杜氏肌营养不良症 (DMD) 的机制，并利用这些知识来推进治疗。治疗呼吸功能不全和其他肌肉退化并发症的进展导致心脏疾病疾病正在成为 DMD 发病和死亡的主要原因。因此，迫切需要确定促进 DMD 相关心脏病的具体致病机制，以便有针对性地可以开发治疗方法。复杂的病理学始于机械受损的肌细胞，但与对疾病进展有重要贡献的继发缺陷交织在一起。纤维化是其中之一 DMD 心脏受累的最早临床表现发生在心室功能障碍之前，表明病理进展早期存在活化的成纤维细胞。成纤维细胞产生细胞外基质包含纤维化疤痕，但尚不清楚它们是否具有其他适应不良功能影响疾病进展。我们的初步研究结果表明，成纤维细胞生长因子 (FGF) 23 对 mdx 小鼠（一种 DMD 遗传小鼠模型）的心脏成纤维细胞增加。 FGF23 升高显着与肾病患者心血管疾病和死亡率相关的重要临床事件相关疾病和一般人群。 FGF23 是一种主要与其共同受体协同作用的激素 Klotho，但也可以刺激非典型细胞靶点的病理信号传导。 FGF23 发挥病理作用通过与 FGF 受体 (FGFR) 4 结合而对心肌细胞产生影响，与 Klotho 无关，Klotho 在心肌细胞中不表达心。我们的中心假设是营养不良的心脏成纤维细胞对心肌细胞产生旁分泌作用通过 FGF23，从而激活 FGFR4，促进 DMD 中的心脏病。我们的初步调查结果表明 Klotho 对 mdx 小鼠具有心脏保护作用，强烈支持我们的假设，即 FGF23 信号传导有助于对心脏重塑具有重要意义。中心假设将通过追求两个全面的具体目标。在目标 1 中，我们将测试 FGF23 是否是心脏成纤维细胞产生的旁分泌因子，可促进使用条件遗传方法结合抗肌营养不良蛋白缺乏的心脏病理学和功能缺陷与离体细胞培养实验。在目标 2 中，我们将确定心肌细胞中的 FGFR4 是否激活使用互补的功能丧失和获得来影响肌营养不良蛋白缺乏的心脏重塑和功能功能遗传方法。拟议的研究具有创新性，因为它预计表明成纤维细胞对心肌细胞发挥调节作用，并将 FGF23/FGFR4 信号传导建立为一种新型致病因子 DMD 的机制。这一贡献意义重大，因为它有望提供强大的机制调节 FGF23/FGFR4 作为治疗 DMD 的治疗靶点的合理性。