Spag6表达降低诱发哮喘气道平滑肌收缩增强及其抑制的研究

Airway smooth muscle (ASM) contraction enhancement is the fundamental feature of asthma. However, the underlying mechanism is still unclear, which results in a lack of treatment from the cause of asthmatic ASM contraction enhancement. We, for the first time, found that the expression decrease of sperm-associated antigen 6 (Spag6) in asthmatic ASM linked to ASM contraction enhancement (indicated by 1 table and 10 figures). Based on these 11 groups of results and our published data (25,49-50), we proposed that: The decrease in Spag6 expression will induce asthmatic ASM contraction enhancement, which mediated by the up-regulation in the function of P2X7、TRPM3 and TRPM6 channels, and these channels can be blocked by bitter tastants, thus, bitter tastants will be the new drug to treat the asthmatic ASM contraction enhancement. We will use Spag6 knock out mouse (non commercial) and the mouse model of asthma, as well as imaging、 patch clamp、 immunohistochemistry、 force measuring and molecular biology techniques, according to the road map indicated by our data, at multiple levels from tissue、cell、molecule and ion, to testify the above hypothesizes. The accomplishment of this proposal will, from a new angle, provide a novel interpretation for the asthmatic ASM contraction enhancement and a new drug for its treatment, which will benefit numerous asthmatic subjects.

气道平滑肌收缩增强是哮喘的基本特征。然而，其形成机理仍不甚清楚，导致针对其起因的治疗措施缺乏。我们首次发现哮喘小鼠气管平滑肌中精子相关抗原6 (Spag6)表达降低与其收缩增强藕联(由正文中1张表格及10幅图中的结果提示)。基于这11组数据及我们发表的资料(25,49-50)，我们提出了本课题的假说：Spag6表达降低将诱发哮喘气道平滑肌收缩增强，此收缩增强是由P2X7、TRPM3及TRPM6通道介导，苦物质可阻断这些通道，因此是抑制哮喘气道平滑肌收缩增强的药物。我们将以Spag6敲除小鼠(非商业化)与哮喘小鼠模型为对象，以成像、patch、免疫组化、张力测量及分子生物学等技术为手段，依据实验结果提示的可行路线图，从组织、细胞、分子及离子多个水平以及气管和肺内大气道多部位求证上述假说。课题完成后将从新的视角为哮喘气道平滑肌收缩增强提供一种新解释及一种新治疗药物，有望惠及众多哮喘患者。

通气受限性疾病，如，哮喘，COPD，患者众多，其一个重要症状是气道高反应，然而其机理尚不清楚，当前治疗药物疗效不佳，并且副作用多而严重，甚至无法使用药物控制的哮喘达到24%。在此背景下，本课题对气道高反应的机理和防治方法进行了探讨，基于预实验结果提示，Spag6与气道高反应相关，此气道高反应是由离子通道介导，苦物质可阻断这些通道，因此是抑制哮喘气道平滑肌收缩增强的药物,这一假说在本研究中得到了证实，成果分别发表于14篇（请参阅附件）及后续的论文中。本研究为气道高反应的机理和防治提供了理论依据，尤其为开发新的气道舒张剂提供了许多潜在的药物或药物前体。