衰老引起的大脑内稳态失调和神经炎症的机理与干预研究

脑衰老引起的自噬水平降低和神经炎症是导致人类多种神经退行性疾病的重要风险因素，但相关机理及其干预的方法尚不清楚。衰老研究一直缺乏有效的哺乳动物模型来研究相关机理。我们通过定量蛋白质组学发现关键蛋白PTEN磷酸酶在脑衰老中发生显著性下调。我们发现PTEN缺失可以激活受体互作蛋白激酶RIPK1并诱导炎症；已知PTEN缺失可以抑制自噬，但机制并不清楚；我们进一步发现棕榈酰转移酶ZDHHC5在衰老中也发生显著性下调，且ZDHHC5可以调控自噬。据此，我们拟采用PTEN条件性缺失的小鼠建立新型哺乳动物衰老模型，并研究PTEN-ZDHHC5轴在大脑选择性自噬中的作用与机理。我们最近的研究证明，抑制衔接蛋白TRADD可以同时激活自噬并抑制RIPK1的激活。我们拟采用PTEN条件性缺失小鼠的衰老模型，通过靶向TRADD激活自噬水平和抑制神经炎症，来研究对衰老引起的神经退行性疾病的发生发展进行干预的可能性。

Aging-induced decline of autophagy and upregulation of neuroinflammation in the brain are two major risk factors that lead to multiple human neurodegenerative diseases. Simultaneously activating autophagy and inhibiting neuroinflammation in aging brain might provide a powerful strategy for the therapeutics targeting neurodegenerative diseases. However, it is not clear whether aging-induced autophagy reduction and neuroinflammation in the brain can be controlled by a common regulatory mechanism due to the lack of a good animal model mimicking human aging. Here we show that PTEN, a phosphatase, was significantly reduced in the aging human brain; we propose that PTEN may regulate selective autophagy in the brain by controlling the protein levels of palmitoyltransferase ZDHHC5, thereby modulate synaptic plasticity and learning and memory; we also found that PTEN deficiency activates receptor interacting protein kinase-1 (RIPK1) and induces RIPK1-dependent inflammation. Our previous study shown that targeting TRADD, an adaptor protein, simultaneously activates autophagy and inhibits RIPK1 activation. We propose that aging-induced decrease of PTEN leads to autophagy reduction and neuroinflammation in human brain. We suggest that PTEN conditional knockout mice may serve as new animal models of human aging. We will explore the underlying mechanisms and function of PTEN-ZDHHC5 axis in regulating autophagy and PTEN-RIPK1 axis in regulating neuroinflammation by using these animal models. Furthermore, we will target TRADD to activate autophagy and inhibit neuroinflammation in these animal models. Our study will provide a strategy for developing novel therapeutics targeting aging-induced learning and memory disorders and neurodegenerative diseases.