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.
