NLRC4基因突变在自身炎症患儿中的炎症反应机制研究

NLR proteins are genome-encoded innate immune sensors which oligomerize to form a complex known as an inflammasome when they sense a pathogen.Mutations in NLR genes can cause activation of the innate immune sensor even when there is no pathogen present. This can cause constant inflammation diseases.We performed exome sequencing, and identified a de novo mutation in the gene NLRC4 from a two year old patient with severe inflammatory disease. This gene encodes an innate immune sensor that recognises the protein from the type III secretion system found in many types of bacteria. Our preliminary data shows thatthe mutation leads to spontaneous activation of the NLRC4 inflammasome.We have preliminary data that this mutation defines a new interface in the structure of NLRC4 that regulates its ability to oligomerize and form an inflammasome complex. We now plan to study this in greater detail and determine the precise mechanism of activation. This will lead us to new discoveries about the function of NLRC4 in response to infection, and for therapy of patients with activation of this pathway. As this new interface on the NLRC4 structure is important for activation, we also propose to screen for small molecules that bind to this site, and should inhibit NLRC4. This will allow us to identify inhibitors of NLRC4 which will be excellent drugs with potential to treat chronic inflammatory diseases and infections.

NLR蛋白是先天免疫感受分子，一旦感受到病原菌入侵，NLR蛋白就会发生齐聚化形成炎性小体。即使在无病原体入侵時，NLR基因的突变亦会使其自我激活而导致持续的炎症及相关病症。本研究始于对自身炎症病人的样本进行外显子测序，首次鉴定出全新的NLRC4基因突变，作为先天免疫感受分子, NLRC4可以识别多种细菌三型分泌系统中的蛋白。我们的初步结果证明该突变可以导致NLRC4的自我激活，该突变使NLRC4的分子结构产生一个新的调控界面，从而改变了NLRC4齐聚化和形成炎症小体复合物的能力。本项目将详细研究该变异所导致的结构变化和自我激活的分子机制。在应对感染反应中，这将有利于探讨NLRC4的新功能，并为因该通路激活而导致的疾病提供新的治疗基础。另外，筛选针对该结合位点的小分子化合物，可以研发抑制NLRC4激活的小分子药物，从而为治疗慢性炎症疾病和感染提供新思路。

NLR蛋白是基因组编码的天然免疫感受分子，一旦感受到病原菌入侵，NLR蛋白就会寡聚化 形成一个叫炎症小体的复合物。NLR基因的突变会导致其在没有病原菌存在情况下被激活，导 致持续的炎症相关病症。本项目始于对自身免疫炎症病人来源的样本进行外显子测序，鉴定出 的全新的NLRC4基因突变，NLRC4基因编码的天然免疫感受蛋白可以识别多种类型细菌的三型分 泌系统中的蛋白。我们的初步结果证明该突变可以导致NLRC4炎症小体的自发激活，并提示该 突变使NLRC4的分子结构产生了一个新的调控界面，从而改变了NLRC4寡聚化和形成炎症小体复 合物的能力。本项目将详细研究该突变导致的结构变化和自发激活的分子机制。这将有利于发 现NLRC4在对感染的反应中的新功能，为治疗由于该通路被激活而导致的疾病提供新的基础， 筛选针对该结合位点的小分子化合物，可以发现抑制NLRC4激活的小分子，从而为治疗慢性炎 症疾病和感染提供新的可能。