慢性肾脏病相关毒素调节酸敏感离子通道1a的功能和机制研究

Chronic kidney disease (CKD) has an overall prevalence and higher co-morbidity of emotion disorder in contrast to other chronic physical disease. It is the major health burden worldwide, but its mechanism remains elusive. As dialysis is hard to improve emotion disorder and remove protein-bound uraemic toxins, protein-bound uraemic toxins is assumed to be the key point involved in mechanism of negative emotion in chronic kidney disease. It has been reported that acid-sensing ion channel 1a (ASIC1a) in the amygdala is the crucial mediator in emotion disorder associated chronic stress. The preliminary results showed that depression and anxiety-related behaviors associated with CKD also depend on ASIC1a in the amygdale and brain derived neurotrophic factor (BDNF) in hippocampus. Indole-3-acetic acid (IAA) was found to be increased in cerebrospinal fluid and serum of CKD mice, which could increase the acid-induced currents by ASIC1a in cultured neurons. We would like to interfere IAA and ASIC1a in the amygdale to discover the mechanism of IAA regulating ASIC1a in the amygdale in emotion disorder with CKD. This project will demonstrate the regulative mechanism of high-level IAA on ASIC1a-BDNF pathway, expend the function of ASIC1a, and provide new drug-targets and strategies to improve life quality of CKD patients.

慢性肾脏病（CKD）患病率高、预后差，比其他慢性疾病更易并发情绪障碍，是目前最严重的公共健康问题之一。目前血液透析技术很难清除肠道菌群产生的蛋白结合毒素，也无法改善CKD并发情绪障碍，推测蛋白结合毒素可能通过作用于神经元膜受体进而参与调控CKD并发情绪障碍。申请人具有长期研究离子通道功能的经验（eLife, 2015; PNAS, 2012），前期结果观察到CKD小鼠脑脊液中增高的蛋白结合毒素吲哚乙酸能增强神经元上酸敏感离子通道1a（ASIC1a）通道功能，进一步实验发现CKD并发情绪障碍依赖于杏仁核ASIC1a-海马神经营养因子（BDNF）通路。项目将通过干预吲哚乙酸和杏仁核ASIC1a，多层面阐明吲哚乙酸对ASIC1a作用的特异性及其调控CKD并发情绪障碍的分子机制。研究将拓展神经系统ASIC1a功能，揭示其内源调控机制，也为治疗CKD并发情绪障碍提供药物靶点。

慢性肾脏病（CKD）患病率高、预后差，比其他慢性疾病更易并发情绪障碍，是目前最严重的公共健康问题之一。目前血液透析技术很难清除肠道菌群产生的蛋白结合毒素，也无法改善CKD并发情绪障碍，推测蛋白结合毒素可能通过作用于神经元膜受体进而参与调控CKD并发情绪障碍。申请人具有长期研究离子通道功能的经验（eLife, 2015; PNAS, 2012），前期结果观察到CKD小鼠脑脊液中增高的蛋白结合毒素吲哚乙酸能增强神经元上酸敏感离子通道1a（ASIC1a）通道功能，进一步实验发现CKD并发情绪障碍依赖于杏仁核ASIC1a-海马神经营养因子（BDNF）通路。项目将通过干预吲哚乙酸和杏仁核ASIC1a，多层面阐明吲哚乙酸对ASIC1a作用的特异性及其调控CKD并发情绪障碍的分子机制。研究将拓展神经系统ASIC1a功能，揭示其内源调控机制，也为治疗CKD并发情绪障碍提供药物靶点。