2015-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643807摘要：藉由活化一群pattern-recognition receptors (PRRs)而產生的先天免疫反應是宿主抵禦微生物病原的第一道防線。在一些促發炎細胞素中，介白素IL-1已證明可以被病原誘導產生，且負責宿主防禦及造成發炎反應的主要功能。產生IL-1需要發炎小體 (inflammasome) 中的caspase-1 活化，進而促使pro-IL-1分解成有活性的終產物，而分泌到細胞外作用。Spleentyrosine kinase (Syk) 是一種脾酪氨酸蛋白激酶，已知在一些PRRs，尤其是C-type lectinreceptors (CLRs)中可以經由受體本身所具有的intracellular immunoreceptor tyrosine-basedactivation motif (ITAM)結構 (如Dectin-1 受體)或連接FcR (如Dectin-2 及Mincle 受體)或DAP12 (如CLECA5A 受體)所含的ITAM 而被活化。雖然一些Syk 的偶和CLRs 受體可以辨識黴菌、分枝桿菌及病毒，但有關CLRs 活化後的功能及參與感染症的病理機制仍相當有限。目前有報導Dectin-1 及Dectin-2 可以辨識白色念珠菌、CLEC5A 可以辨識登革病毒及日本腦炎病毒、而Mincle 可以辨識分枝桿菌。雖然發炎小體過度活化caspase-1 而產生大量IL-1與感染疾病導致的死亡非常有關，但目前仍不清楚Syk 如何調控病原所活化的三種發炎小體(NLRP3、NLRC4、AIM2)。同樣也不清楚各種不同病原是經由何種CLRs 來活化發炎小體。因此受體及發炎小體之間的專一作用會依不同病原來決定。本研究的目的主要是探討Syk 參與白色念珠菌、登革病毒、日本腦炎病毒、流感病毒、牛痘病毒、巨噬細胞病毒所活化的發炎小體的分子作用機制，並了解參與的CLRs (Dectin-1、Dectin-2、CLECA、Mincle)種類。此計畫有三個研究目標包括：目標一：探討Syk 在NLRP3、NLRC4、AIM2 發炎小體的活化角色。目標二：探討Syk 調控NLRP3、NLRC4、AIM2 發炎小體的分子機轉。目標三：探討Syk 偶合CLRs 受體媒介不同病原活化發炎小體的作用。此研究結果可以解開病原產生IL-1的真正作用分子機制，且提供治療感染疾病的新治療標靶。<br> Abstract: The innate immune response triggered by pattern-recognition receptors (PRRs) is the first line ofa host’s defense against microbial pathogens. Interlukin-1 (IL-1 is a key pro-inflammatory factorinduced by various pathogens and is a central orchestrator of immunity for host defense andinflammatory diseases. Regulation of IL-1 production is through a complicated mechanism andrequires triggering of proteolytic pro-IL-1 processing to produce bioactive IL-1 via activation ofpro-caspase-1-containing multiprotein complexes called inflammasomes. Spleen tyrosine kinase (Syk)is a major and common upstream signaling molecule of many types of PRRs, in particular the C-typelectin receptors (CLRs) which contain the intracellular immunoreceptor tyrosine-based activationmotif (ITAM) in either the cytoplasmic regions (e.g. Dectin-1) or the receptor adaptors like FcR (e.g.Dectin-2, Mincle) and DAP12 (e.g. CLEC5A). Even though some Syk-coupled CLRs have beenidentified to recognize fungi, mycobacteria and viruses, functional studies regarding how CLRsrecognize microorganism and contribute to the pathogenesis of human infectious diseases are stilllimited. In this aspect, Dectin-1 and Dectin-2 can recognize fungus C. albicans, CLEC5A canrecognize Dengue virus (DV) and Japanese encephalitis virus (JEV), and Mincle can recognizemycobacteria. Inflammasome-mediated caspase-1 activation leading to excess secretion of matureIL-1 has been demonstrated involving in the inflammatory responses associated with mortality ofmany infectious conditions. However, thus far it is largely unknown how Syk regulates NLRP3,NLRC4 and AIM2 inflammasomes activation induced by pathogens. It also remains unclear the rolesof CLRs in recognizing pathogens and coupling Syk to induce inflammasome activation and IL-1secretion. The aim of this study is to explore the role and molecular nature of Syk as well as CLRs (e.g.Dectin-1, Dectin-2, Mincle, CLEC5A) in modulating three types of inflammasome activation causedby various pathogens (e.g. Candida, DV, JEV, influenza virus, vaccinia virus and MCMV). Threespecific aims are included for this study: Aim 1: Determine the roles of Syk in IL-1 productionthrough NLRP3, NLRC4 and AIM2 inflammasomes activation; Aim 2: Determine the molecularmechanisms of Syk in regulating NLRP3, NLRC4 and AIM2 inflammasomes activation; Aim 3:Determine Syk-coupled CLRs responsible for the pathogens-induced inflammasome activation.The functional link from pathogen-recognized CLRs to inflammasome activation is a new researchfield. The information obtained from this study is expected to unravel the mystery of pathogen-elicitedIL-1 production that is controlled by Syk, the converged signaling molecule of various PRRs.Moreover, the information of this study can not only bring scientific impact in host immunity but alsoprovide a framework for the therapeutic targeting of inflammasome in many kinds of infectiousdiseases.