Transthyretin异常沉积参与颈动脉硬化斑块形成作用机制研究

Carotid atherosclerotic plaque (CASP) formation is the major risk factor in ischemic stroke. Research into the disease has led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation. Despite the resent advances, we still lack definitive evidence to show comprehensive processes of atherosclerosis. Exploration of the underlying mechanism still present challenges. We have established a distinctive site-specific method to investigate the proteomic profiles among different regions of carotid atherosclerotic plaque as previously published. Transthyretin (TTR) showed a site-specific alteration in different stages of plaques. TTR tetramer misfolding and amyloid deposite in carotid plaque were detected and validated by situ Congo Red and immunofluorescence combined staining in further research. TTR were suggested to involve in reverse cholesterol transport in macrophages, but the mechanistic links between TTR and atherogenesis remain unclear.Our project intended to investigate the hypotheses that TTR misfolding and amyloid deposite regulate the process of plaque development, TTR stabilizer Tolcapone may present potential protective effect in vivo and vitro.Understanding underlying mechanism will provide further insight into atherosclerosis and could lead to new clinical applications.

颈动脉硬化斑块（CASP）的形成进展过程因与缺血性脑血管病直接相关而严重危害人类健康。探索参与CASP形成的相关细胞分子调控机制具有重要意义。课题组前期对CASP的蛋白质组解析中发现，血浆转甲状腺素蛋白（Transthyretin, TTR）可沉积表达于CASP并与其病理改变分期相关，但其参与CASP形成的机制不清。在进一步的临床样本验证中发现，TTR在CASP的位点特异性表达同时伴有原位淀粉样蛋白沉积。有相关体外研究显示TTR异常沉积形成淀粉样变可影响巨噬细胞内胆固醇的外流过程，但目前尚无该过程参与CASP形成的直接证据。本项目拟从相关研究结果及课题组前期工作线索切入，结合体内外模型，应用新型血浆TTR稳定剂行功能干预，研究TTR异常沉积在CASP进程中的生物学作用；重点研究TTR调控巨噬细胞相关脂蛋白吞噬及胆固醇外流过程参与CASP进程的分子机制，为后续转化医学研究奠定基础。