Cardiac myofibroblasts in autoimmune associated CHB

描述（由申请方提供）：抗SSA/Ro-SSB/La抗体的作用 在先天性心脏传导阻滞（CHB）的发病机制中，的 这种情况涉及房室结（AV）损伤， 通过阶段，与最终的结果是纤维化的节点， 不可逆性三度传导阻滞拟议的研究将审查 心脏成纤维细胞可能是发病机制中的"胎儿因素" 自身免疫相关的慢性乙型肝炎在正常情况下，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，本发明还提供了一种方法， 通常胎儿会愈合而不会留下疤痕，并且在伤口愈合期间， 成纤维细胞瞬时变成肌成纤维细胞，其参与了 肉芽组织成熟。拟议的研究将确定是否 成纤维细胞的持续活化（即，转分化为 持久性肌成纤维细胞）参与自身抗体的效应期 介导的损伤，其中成纤维细胞从正常维持转换为 病理生理作用导致房室结最终被 纤维组织具体目标1中的实验旨在解决 抗SSA/Ro-SSB/La抗体诱导读出的能力， 纤维化（成纤维细胞活化和增殖）。具体目标2将 确定异常成纤维细胞表型（即，肌成纤维细胞）是 反映为小GTP酶Racl和RhoA的异常信号转导。 Specific Aim将检查母体自身抗体是否诱导损伤 在体内模型中启动心脏肌成纤维细胞的持续存在 利用表达人52 β Ro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 转化为未经检查的增殖肌成纤维细胞构成了一个"胎儿因素"， 自身免疫性CHB可能提供了对自身抗体介导的机制的见解， 组织损伤在这个危及生命的临床问题。

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.