抗HuD抗体引起肠易激综合征肠神经元凋亡机制及靶向干预研究

肠易激综合征（IBS）发病机制复杂，申请者前期发现IBS患者血清抗肠神经元抗体（主要为抗HuD抗体）体外可诱发神经元凋亡；抗HuD抗体被动转移大鼠模型表现出IBS临床特征。尚不清楚抗HuD抗体阳性IBS患者肠神经元组织学改变。结合文献及前期研究提出假说：抗HuD抗体被动转移大鼠模型肠神经元存在凋亡现象，其机制可能是抗HuD抗体阻碍HuD蛋白与神经元生长发育密切相关的靶mRNA结合，造成靶mRNA稳定性和数量下降；通过中和、清除抗HuD抗体、增加HuD蛋白表达和抗神经元凋亡干预可能治疗部分IBS。本项目检测抗HuD抗体被动转移模型大鼠肠神经元凋亡改变，检测HuD蛋白重要靶mRNA表达量，最终中和、清除抗HuD抗体，增加HuD蛋白表达和抗神经元凋亡干预后观察肠神经元凋亡的变化，阐明IBS发病涉及抗HuD抗体导致的肠神经元凋亡及分子机制，从自身免疫性肠神经病变角度丰富IBS的发病机制和治疗策略。

The pathogenesis of irritable bowel syndrome (IBS) is complicated. The applicant has showed anti-enteric neuronal antibodies (mainly anti-HuD antibody) in serum of IBS patients could evoke neuronal apoptosis in vitro and rat models established by passive transfer of anti-HuD antibody showed clinical characteristics of IBS. It is unclear the histological changes of enteric neurons of anti-HuD antibody positive IBS patients. Combined with literature and previous studies, the applicant proposed a hypothesis: neuronal apoptosis exists in enteric nervous system of rat models established by passive transfer of anti-HuD antibody; the possible pathogenesis may be anti-HuD antibody hinders the binding of HuD protein and its target mRNA which are closely related to neuronal growth and development, and causes the decrease of mRNA stability and expression; neutralization, removal of anti-HuD antibody, up-regulation of HuD protein and anti-neuronal apoptosis intervention may have potential therapeutic roles in partial IBS. The current project investigates enteric neuronal apoptosis changes of rat models established by passive transfer of anti-HuD antibody; tests the expression of target mRNA of HuD protein; observe enteric neuronal apoptosis changes after neutralization, removal of anti-HuD antibody, up-regulation of HuD protein and anti-neuronal apoptosis intervention. The project aims to demonstrate the pathogenesis of IBS is related to enteric neuronal apoptosis caused by anti-HuD antibody and its molecular mechanism. Thus, we supplement IBS pathogenesis and treatment strategy from autoimmune enteric neuropathy level.