Cardiac myofibroblasts in autoimmune associated CHB

描述(申请人提供)：抗SSA/Ro-SSB/La抗体的作用 在先天性心脏传导阻滞(CHB)的发病机制上已有很好的认识。这个 情节涉及房室结(AV)的损伤，进展 通过分期，最终结果是结节和 不可逆三级封堵。建议的研究将检视 心脏成纤维细胞在发病机制中是“胎儿因子”的可能性 与自身免疫相关的慢性乙肝。在正常情况下，成纤维细胞 维持心脏组织的粘弹性，这是一种被动的属性 由来自组织成纤维细胞的弹性蛋白和胶原蛋白提供。此外, 通常情况下，胎儿愈合时没有疤痕，在伤口愈合过程中 成纤维细胞瞬间变成肌成纤维细胞，参与一种 肉芽组织成熟。拟议的研究将确定一项 成纤维细胞的持续激活(即，转分化为 持续性肌成纤维细胞)参与自身抗体的效应阶段 介导性损伤，其中成纤维细胞从正常维持切换到 导致房室结最终被替换的病理生理作用 纤维组织。具体目标1中的实验旨在解决 抗SSA/Ro-SSB/La抗体诱导读数的能力 纤维化(成纤维细胞活化和增殖)。特定目标2将 确定异常的成纤维细胞表型(即肌成纤维细胞)是否 小的GTP酶Rac1和RhoA的异常信号转导反映了这一点。 具体目的是检查母体自身抗体是否导致损伤 在活体模型中启动心肌成纤维细胞的持续性 利用表达人52βRo核糖核蛋白的转基因小鼠 心脏。确定心脏成纤维细胞的转分化是否 无节制地增殖的肌成纤维细胞构成了 自身免疫性慢性乙型肝炎可能为自身抗体介导的机制提供新的见解 组织损伤在这个危及生命的临床问题上。

DESCRIPTION (provided by applicant): A role for anti-SSA/Ro-SSB/La antibodies in the pathogenesis of congenital heart block (CHB) is well established. The scenario involves injury at the atrioventricular (AV) node which progresses through stages, with the final outcome being fibrosis of the node and irreversible third degree block. The proposed studies will examine the possibility that cardiac fibroblasts are a "fetal factor" in the pathogenesis of autoimmune-associated CHB. Under normal circumstances, the fibroblast maintains the cardiac tissue's viscoelasticity, a passive attribute which is provided by elastin and Collagen derived from tissue fibroblasts. In addition, normally a fetus heals without scarring, and during wound healing the fibroblast transiently becomes a myofibroblast which is involved in a maturation of granulation tissue. The proposed studies will determine whether a persistent activation of the fibroblast (i.e., transdifferentiation to a persistent myofibroblast) participates in an effector phase in the autoantibody mediated injury, where the fibroblast switches from normal maintenance to a pathophysiological role leading to the ultimate replacement of the AV node by fibrotic tissue. The experiments in Specific Aim 1 are designed to address the capacity of anti-SSA/Ro-SSB/La antibodies to induce readouts which relate to fibrosis (fibroblast activation and proliferation). Specific Aim 2 will determine whether the abnormal fibroblast phenotype (i.e., myofibroblast) is mirrored by abnormal signal transduction by small GTPases Racl and RhoA. Specific Aim will examine whether injury induced by maternal autoantibodies initiates the persistence of cardiac myofibroblasts in an in vivo model exploiting transgenic mice that express human 52beta Ro ribonucleoprotein in the heart. Establishing whether the transdifferentiation of cardiac fibroblasts into unchecked proliferating myofibroblasts constitutes a "fetal factor" in autoimmune CHB may provide insights into the mechanism of autoantibody-mediated tissue injury in this life-threatening clinical problem.