Cofilin-Actin线粒体锚定信号分子通过调节呼吸中枢pre-BötC可塑性参与阻塞性睡眠呼吸暂停的机制研究

阻塞性睡眠呼吸暂停（OSA）是最常见的睡眠呼吸紊乱疾病，目前缺乏有效的治疗手段。急性间断性缺氧（AIH）可诱导膈神经和舌下神经产生长时程易化（LTF），是反映呼吸可塑性的电生理指标。我们已经发现呼吸中枢pre-BötC参与呼吸可塑性调控，突触后线粒体作用至关重要，尤其发现actin丝状结构将线粒体与突触后膜连接，提示actin细胞骨架蛋白参与线粒体突触锚定，但作用机制目前不清楚。本项目拟建立温和AIH→LTF和严重慢性间断性缺氧（CIH）→OSA动物模型，结合形态学、电生理学、分子生物学等技术，通过干预actin结合蛋白cofilin，调控actin聚合-解聚状态，探讨pre-BötC突触后actin细胞骨架蛋白参与线粒体可塑性调控的功能意义，明确线粒体突触后锚定的LIMK-cofilin-actin信号机制，为线粒体参与呼吸可塑性调控提供实验依据，为OSA提供潜在的治疗对策。

Obstructive sleep apnea (OSA) is the most common disease in sleep breathing disorders that lacks effective clinical treatment so far. Acute intermittent hypoxia (AIH) induces long-term facilitation (LTF) of phrenic and hypoglossal nerves, representing physiological characteristic of respiratory plasticity. We have demonstrated that the pre-Bötzinger complex (pre-BötC), the kernel of respiratory generator is responsible for the respiratory plasticity. Mitochondria in postsynaptic dendrites play a critical role in the process. In particular, we found that actin filamentous structures link mitochondria to the postsynaptic membrane, suggesting actin cytosteletal protein in mediation of postsynaptic mitochondrial anchoring. However, the mechanism underlying mitochondrial anchoring remains unknown. In combination of morphological, electrophysiological, and molecular biological approaches, the present study was aimed to explore the role of cofilin, an actin binding protein, in control of actin polymerization- depolymerization that may contribute to mitochondrial plasticityin the pre-BötC in animals exposed to daily AIH or chronic intermittent hypoxia (CIH) challenge. We wish to clarify the mechanism of LIMK-cofilin-actin underlying postsynaptic mitochondrial anchoring in the pre-BötC. This study will provide experimental evidence of mitochondria in participation in respiratory plasticity, and further seek for potential therapeutic strategies for OSA.