水通道蛋白4在老年性聋血迷路屏障退行性病变中的作用及机制研究

The blood-labyrinth barrier (BLB) is a physical barrier that controls exchanges between blood and the intrastitial space in the cochlea, which involving regulation of cochlear homeostasis and promise of normal function of inner. Our previous experiment data showed that there was significant degeneration on the BLB of presbycusis mice, but the mechanism is not clear. In our recent study we discovered AQP4 expressed in the surface membrane of Perivascular resident macrophage-like melanocytes (PVM) that surround vascular endothelia.Suppression of AQP4 causes reduction of gap junction protein CX43 between PVM and EC, increase the permeability of BLB, indicating that the AQP4 is essential for maintaining BLB integrity.However,there were few reports about the AQP4 role in the presbycusis mice. So we address the hypothesis that: AQP4 may paly an important role in pathological mechanism of age-related disruption of BLB by communicating with gap junction and maintaining PVM physiology.To prove our hypothesis, we will observe the important role of AQP4 in the regulation of integrity of BLB from molecular ,cellular, body level respectively,explore the mechanism of AQP4 regulating CX43 , examine the role of AQP4 in degeneration on the BLB of presbycusis mice. This will provide new thought for AQP4-targeted therapies for treatment of presbycusis.

血迷路屏障（BLB）是介于血液和内耳迷路液间的一种生理屏障，是维持内耳稳态，保证内耳正常功能的重要结构。我们前期实验证实老年性聋小鼠BLB存在明显的退行性病变，但具体机制尚不明确。我们预实验发现，BLB组成细胞血管旁定居的巨噬细胞样黑色素细胞（PVM）膜表面表达水通道蛋白4（AQP4），抑制AQP4表达可致PVM形态发生改变，PVM与内皮细胞间缝隙连接蛋白CX43表达下降，BLB透通性改变，示AQP4在BLB完整性调控中起重要作用。迄今AQP4在老年性聋中的作用知之甚少，据此我们提出假说：AQP4通过调控PVM特性，介导CX43表达，参与老年性聋BLB退行性病变的作用机制。为验证这一假说，我们拟从分子、细胞、动物整体等多层次明确AQP4在BLB完整性调控中的作用；探讨AQP4调控CX43表达机制；揭示AQP4在老年性聋BLB退行性病变中的作用，为以AQP4为靶点治疗老年性聋提供新思路。