神经退行性病变是糖尿病常见并发症之一。胰岛素受体酪氨酸激酶底物IRSp53主要分布在颅内，在促进神经突触的形成和维持神经细胞结构上发挥重要作用。β淀粉样蛋白前体(APP)代谢障碍产生的有毒寡肽Abeta在细胞内的聚集是负向影响认知功能的主要原因。目前IRSp53调控APP作用机制尚不清楚。申请人前期发现在神经元细胞中IRSp53与APP表达呈负相关，提示IRSp53及APP可能共同参与了糖尿病神经退行性病变并发症的发生。项目拟利用妊娠糖尿病大鼠及IRSp53敲除大鼠，探讨IRSp53/PI3K/APP信号通路正负反馈调节规律，阐明IRSP53介导PI3K/APP通路参与神经退行性病变作用的新机制，为糖尿病神经退行性病变治疗提供新靶点和新依据。

Neural degenerative diseases are common complications of diabetes. IRSp53, a substrate of insulin receptor tyrosine kinase, mainly localizes in intracranial where ISRp53 plays an important role in promoting the formation of synapses and maintaining the structure of nerve cells. Oligopeptide Abeta is a toxic metabolism production of beta amyloid precursor protein that is a major cause of negatively affective cognitive function. The regulation of IRSp53 in APP remains unknown. We previously found that the expression of IRSp53 was negatively correlated with APP expression, strongly indicating that both IRSp53 and APP may participate in the neural degenerative diseases of diabetes complications. This project will explore the positive and negative regulator of the signaling pathway of IRSp53/PI3K/ APP using gestational diabetes rats and the IRSp53 knockout rats to clarify that the PI3K/APP pathways mediated by IRSp53 might involve in neural degenerative diseases. The proposal will provide new targets and basis for diabetes with neurodegeneration.