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Nat Med:MLCK1——预防胃肠疾病的新策略

2019-04-04 佚名 生物探索

研究发现通过特异性针对MLCK1的维持和恢复肠上皮屏障功能的小分子Divertin,或许可以预防和治疗胃肠疾病。这项研究是由芝加哥大学/哈佛大学医学院Jerrold R. Turner教授研究组和苏州大学剑桥-苏大基因组资源中心何伟奇教授研究组共同合作完成。

食物过敏、乳糜泻、炎症性肠病(IBD)、腹泻以及其他肠道疾病有一些共同之处:与肠粘膜屏障功能损伤有关。

肠粘膜上皮屏障——肠内细胞的重要内层,在摄入营养物的同时必须保证肠道发生炎症时能够阻止致病微生物的入侵。尽管目前引发肠疾病的具体分子机制尚不清楚,但先前的研究发现,一种称为肌球蛋白轻链激酶(MLCK)的酶起着至关重要的作用。然而,MLCK对于肠上皮细胞和其他类细胞中的关键功能也是必需的,比如维持肠平滑肌收缩和肠道蠕动等。因此直接抑制MLCK行不通,搞不好它会产生大量的毒性作用和全身副作用。

但是办法总比困难多,由芝加哥大学/哈佛大学医学院Jerrold R. Turner教授研究组和苏州大学剑桥-苏大基因组资源中心何伟奇教授研究组组成的合作小组宣布他们开发出一种替代方法,相关文章发表在Nature Medicine上。研究人员发现通过特异性针对MLCK1的维持和恢复屏障功能或可预防和治疗胃肠疾病。

“这是一种全新的、无毒副作用的恢复肠道屏障功能和治疗炎症性肠病的方法。” 本研究的作者、哈佛医学院的Jerrold Turner说。

其他亚型的MLCK遍布于肠道内壁、各种上皮细胞和平滑肌,而MLCK1亚型在绒毛状肠细胞和相应的结肠表面细胞中呈现高表达。为了奠定只针对MLCK1的基础,Turner和他的团队解决了该区域区别于其他亚型的晶体结构。然后,他们利用计算机模型筛选了大约140,000个分子,寻找一个可以像锁上的钥匙一样进入这个区域的分子。

最终,研究小组发现了一种适配分子,并将其命名为Divertin。Divertin(因其将MLCK1从调控屏障的细胞内位点转运而得名)可防止炎症诱导的屏障缺失而不损害上皮细胞和平滑肌中的关键MLCK酶功能。在炎症性肠病和腹泻的小鼠模型中,Divertin纠正了屏障功能障碍并降低了疾病严重程度。当预防性给予时,Divertin可预防疾病的发生和进展。这表明Divertin可能是一种新的非免疫抑制手段,可以维持IBD患者病程缓解和预防疾病爆发。

Turner和同事指出,靶向MLCK1防止屏障缺失、恢复正常功能同样适用于其它因上皮屏障损伤导致的疾病,包括乳糜泻、过敏性皮炎、肺部感染、急性呼吸窘迫综合征、多发性硬化和移植物抗宿主疾病(GVHD)。在最近发表在Journal of Clinical Investigation上的一项研究中,这个研究小组提出了证据,证明MLCK推动了GVHD的进展。GVHD是一种并发症,在移植后,当供体免疫细胞开始攻击受体的器官时,可能会出现这种并发症。虽然Divertin没有在GVHD中实验,但数据表明它可能是一种有效的治疗方法。

“我们的研究表明,MLCK1是保持肠道疾病及其他疾病上皮屏障功能的可行靶点,” Turner说,“这种治疗方法可能有助于打破引发众多慢性疾病的炎症循环。”

原始出处:

W. Vallen Graham, Weiqi He, Amanda M. Marchiando, et al. Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis. Nature Medicinevolume 25, pages690–700 (2019) .

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