晚发型多酰基辅酶A脱氢酶缺乏症（MADD）伴感觉神经病是一种最近被认识的致残性疾病，其感觉神经受累的机制尚不清楚。RhoT是一种Rho样小GTP酶，能与多种蛋白因子直接发生作用，对神经细胞内线粒体动力学和能量代谢有重要的调节作用。我们的前期研究发现晚发型MADD伴感觉神经病患者的感觉神经细胞内存在异常的氧化应激和线粒体异常，RhoT蛋白可能是其中重要的交集靶点。本课题拟采用RNA干扰和腺病毒包装质粒进行多种细胞和动物实验，研究氧化应激状态下RhoT蛋白介导的线粒体运输、线粒体分裂融合、能量代谢通路的改变规律，同时采用特异性通路RNA芯片技术和二维蛋白电泳技术，对病变神经细胞的表观遗传学和蛋白组学展开研究。探讨周围感觉神细胞内脂肪酸β氧化异常，通过RhoT蛋白的串话从多条通路促发细胞内线粒体异常与能量代谢障碍的病理过程，揭示晚发型MADD伴感觉神经病的致病机制，为该病的治疗提供可能的靶点。

Late-onset multiple acyl-coA dehydrogenation deficiency with sensory neuropathy (MADD-NS) is a disabling disorder that has been recently recognized in China. However, the pathogenic mechanisms of late-onset MADD-NS are still unclear. RhoT is a Rho-like small GTPase that can interact directly with a variety of proteins, and plays an important regulatory role in mitochondrial dynamics and energy metabolism in neuronal cells. In our preliminary study, oxidative stress and mitochondrial abnormalities are found in sensory neuronal cells of late-onset MADD-NS, and RhoT may be one of the important convergent factors. Therefore, we will establish several cell and animal models by vector transfections, RNA interference, and adeno-associated virus mediated vectors injections, and then explore the pathways caused by oxidative RhoT associated with mitochondrial transport, mitochondrial fission/fusion, and metabolism changes. Meanwhile, we will perform epigenetic and proteomic researches in affected neuronal cells through specific-pathway RNA chip and two-dimensional protein electrophoresis. Owing to the abnormalities of β-oxidation in sensory peripheral nerve, Rho-T crosstalk may be associated with mitochondrial dysfunctions and metabolism abnormalities in late-onset MADD-NS. The research about the pathogenic mechanisms will provide possible therapeutic targets for late-onset MADD-NS.