Interplay between skeletal muscle catabolism and remodeling of arteriovenous fistulae via YAP1/TAZ signaling

总结 动静脉瘘（AVF）是一种人工建立的动脉和 静脉，是慢性肾脏病（CKD）血液透析患者的生命线。 然而，60-65%的AVF在创建后1年内失败，导致严重的健康风险， 给患者带来沉重的经济负担。放置或护理血管通路的费用超过2.8美元 亿元/年。虽然已经进行了多项临床试验，但没有可行的治疗方案 被发现了我们的长期目标是确定细胞和分子机制， AVF成熟失败，因此可以制定预防和治疗AVF的治疗策略 失败早期研究表明，CKD诱导的新生内膜（血管内膜增厚） 层）形成和血管纤维化是导致AVF成熟失败的主要危险因素。 最近，我们发现尿毒症小鼠骨骼肌钙蛋白之间的串扰可能是 与AVF功能衰竭有关。我们的初步结果表明，肌肉生长抑制素产生于 尿毒症小鼠骨骼肌刺激YAP 1/TAZ（转录调节因子）的表达 参与细胞增殖的基因），其可以促进血管平滑肌的激活 细胞（VSMCs）和外膜间充质干细胞（MSC）分化为 肌成纤维细胞这些反应导致细胞外基质蛋白的增加和进行性炎症。 血管纤维化细胞外基质的硬度激活YAP 1/TAZ，其形成“前向 反馈回路”。结果是增殖、迁移和炎症的增强， AVF成熟失败。因此，我们假设抑制肌肉生长抑制素或YAP 1/TAZ 将阻止VSMC活化和MSC分化为肌成纤维细胞，从而改善AVF 功能协调发展的本申请中提出的具体目标将调查该假设的有效性。 在目的1中，我们将检查使用中和肽体的肌生长抑制素抑制对肌生长的影响。 新生内膜细胞和AVF纤维化。目的2和3将分析YAP 1和 TAZ敲低Myostatin诱导的VSMC活化和MSC转分化 并评估FDA批准药物Verteporfin是否局部抑制YAP 1活化 抑制CKD诱导的小鼠AVF衰竭。成功完成这些研究将导致 开发新的治疗策略来预防和治疗透析中的AVF失败 患者

Summary Arteriovenous fistula (AVF), an artificially created direct connection between an artery and vein, is the life line for hemodialysis patients suffering from chronic kidney disease (CKD). However, 60-65% of AVFs fail within 1 year of their creation resulting in serious health risks and heavy financial burden to patients. The costs of placing or caring for vascular access exceed $2.8 billion/year. Although, multiple clinical trials have been performed, no viable treatment options have been uncovered. Our long term goal is to identify the cellular and molecular mechanisms of AVF maturation failure so that therapeutic strategies can be developed to prevent and treat AVF failure. Earlier studies demonstrated that CKD-induced neointima (thickening of inner vascular layer) formation and vascular fibrosis are the leading risk factors causing AVF maturation failure. Recently, we found the crosstalk between skeletal muscle catabolism in uremic mice could be related with AVF function failure. Our Preliminary results indicated that myostatin generated in skeletal muscle in uremic mice stimulated the expression of YAP1/TAZ (transcriptional regulators of genes involved in cellular proliferation) which can promote activation of vascular smooth muscle cells (VSMCs) and differentiation of adventitial mesenchymal stem cells (MSCs) into myofibroblasts. These responses result in increased extracellular matrix proteins and progressive vascular fibrosis. The stiffness of extracellular matrix activates YAP1/TAZ which forms a “forward feedback loop”. The result is the enhanced proliferation, migration, and inflammation which lead to AVF maturation failure. We therefore hypothesize that inhibition of myostatin or of YAP1/TAZ will block VSMC activation and MSC differentiation into myofibroblasts resulting in improved AVF functions. Specific Aims proposed in this application will investigate the validity of this hypothesis. In Aim 1 we will examine the effects of myostatin inhibition using a neutralizing peptibody on neointima cells and AVF fibrosis in CKD mice. Aim 2 and 3 will analyze the effects of YAP1 and TAZ knock down on myostatin induced VSMC activation and MSC transdifferentiation in vitro and in vivo, and evaluate if local inhibition of YAP1 activation by FDA-approved drug, Verteporfin suppresses CKD–induced AVF failure in mice. Successful completion of these studies will lead to the development of new therapeutic strategies to prevent and treat AVF failure in dialysis patients.