HSP90通过HIF1α调控BICC1参与抑郁症复发的分子机制

抑郁症是一种慢性且易复发的精神疾病，对其复发机制知之甚少。前期发现HSP90、HIF1α及BICC1可能作为抑郁症复发相关的分子标志物，但其相互调控关系及参与复发的分子机制仍未阐明。基于前期发现：1.BICC1过表达可能通过GSK3β信号通路介导AMPA受体转运异常调控抑郁样行为；2.BICC1的表达可能受到HIF1α的调控；3.HSP90降低HIF1α泛素化降解。我们提出：HSP90通过HIF1α调控BICC1过表达参与抑郁症复发的调控机制。本项目拟采用抑郁复发病例、复发动物模型、GSK3β9A/9A敲入小鼠、HSP90与BICC1敲减与过表达手段对复发中HSP90通过HIF1α调控BICC1过表达的分子机制及诱导AMPA受体转运与突触可塑性障碍的病理机制完整阐明；进一步基于上述机制提出复发预防与治疗的干预方案。本研究将为阐明抑郁症复发的新型分子标记、分子机制及干预策略提供理论基础。

Major depressive disorder (MDD) is a prevalent disease that is recurring, and little is known about the mechanism of recurrence. Our preliminary studies show that HSP90, HIF1α and BICC1 may be specific molecular markers associated with MDD recurrence. However, the regulation relationship between each other and the molecular mechanism involved in recurrence have not been clarified. The previous findings demonstrated that stress-induced BICC1 overexpression may be involve in the depressive-like phenotype dependent on AMPA receptor trafficking mediated by GSK3β signaling pathway. In addition, the BICC1 promoters may be regulated by the HIF1α. Furthermore, we found that HIF1α ubiquitination degradation mediated by HSP90. Herein, the goal of the proposed project is to uncover the role and involvement mechanism of HSP90, HIF1α and BICC1 in the MDD recurrence. The recurrent MDD and first-episode MDD, stress-induced recurrence mouse model,GSK3β 9A/9A knock in mice, virus-mediated HSP90 and BICC1 knock-down and overexpression were used to clarify whether HSP90 mediate HIF1α-regulated BICC1 overexpression and further induced dysfunction of AMPA receptor trafficking and synaptic plasticity in MDD recurrence. Importantly, further drug intervention schemes for recurrence prevention and treatment are proposed based on the above mechanisms. We expect our effort in identifying elucidating biomarkers, novel mechanisms underlying MDD recurrence to provide unmet therapeutic opportunities in treating depression.