基于中枢胰岛素抵抗探讨自噬失调对肾虚阿尔茨海默的影响及机制研究

肾精亏虚是AD发病的关键病机。现代中医学研究证明，肾虚与细胞自噬功能失调密切相关，基于神经细胞自噬异常探讨AD的机制及治疗已成为基础及临床关注的热点。最新研究发现，自噬失调与胰岛素抵抗关系密切，增强自噬可减轻胰岛素抵抗。课题组前期研究证实在AD模型细胞及血管内皮细胞自噬相关基因Atg7表达降低时，胰岛素介导的IRS/PI3K/Akt信号通路也出现了抑制，出现胰岛素抵抗，后者是AD发病的重要机制。由此提出如下假说：肾精亏虚时，神经元的自噬功能缺陷，Atg7表达降低，抑制IRS/PI3K/Akt信号通路，发生中枢胰岛素抵抗，导致AD的发生发展。本研究拟以小鼠模型及细胞模型为研究对象，以自噬驱动的IRS/PI3K/Akt信号通路为切入点，观察肾虚AD状态下神经元自噬的改变及其对胰岛素抵抗的影响及机制，阐明自噬影响AD的关键途径、环节及分子，揭示补肾填精法的效应机制，丰富“肾藏精生髓”的科学内涵。

Deficiency of kidney essence is the key pathogenesis of AD. Modern Chinese medicine research has proved that kidney deficiency is closely related to the dysfunction of autophagy. Based on the abnormal autophagy of neurons, the mechanism and treatment of AD have become the focus of basic and clinical attention. The latest research has found that autophagy is closely related to insulin resistance, and the enhancement of autophagy reduces insulin resistance. Previous studies have confirmed that cell autophagy related gene Atg7 expression decreased in the AD model cell and endothelial, the insulin mediated IRS/PI3K/Akt signal pathway also inhibited, showing insulin resistance, which is an important mechanism of AD pathogenesis. The hypothesis is as follows: when the deficiency of kidney essence is deficient, the neuron's autophagy function is deficient, the expression of Atg7 is reduced, the IRS/PI3K/Akt signal pathway is inhibited, the central insulin resistance is produced, and the development of AD is induced. This study is intended to animal model and cell model as the research object, the IRS/PI3K/Akt signal pathway drived autophagy as a point, to observe the changes of neuronal autophagy deficiency under the condition of AD and its effects on insulin resistance and its mechanism, clarify the key way and molecular mechanism of autophagy, reveal the effect mechanism of tonifying kidney and essence method , and rich scientific connotation of “the Kidney Stores the Essence, Produces the Marrow ”.