2012-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643463摘要：先天性免疫系統負責辨認入侵的病原並且啟動宿主的防禦機制，而其中巨噬細胞因為能夠直接的偵測、消滅病原並且將此入侵訊號傳達給其他細胞，所以在先天性免疫系統中扮演著十分早期且關鍵的角色。相對地，巨噬細胞也成為許多病原逃避宿主免疫系統偵查的阻斷目標，例如炭疽桿菌能夠促進巨噬細胞的自殺性死亡，使宿主先天性免疫系統受到抑制。不過，巨噬細胞若無法進行自殺性死亡，則會造成急性和慢性的發炎反應。因此，巨噬細胞自殺性死亡需受到精準的調控，然而，現在對於巨噬細胞如何調控自殺性死亡的機制仍然不完全清楚。藉由研究炭疽桿菌造成巨噬細胞自殺性死亡的機制，我們發現p38 MAPKs和NF-B這兩條路徑的活化可以抑制上述巨噬細胞自殺性死亡的現象，而PKR (dsRNA responsive protein kinase)則為一重要的促進因子。基於TLRs對於巨噬細胞的活化具有很重要的影響，並可引發其活化後續之生理反應, 本研究計畫旨在闡明巨噬細胞上TLR4之活化對於病原引起的自殺性死亡有何影響，藉由探討NF-kB和 p38訊息傳遞如何啟動抗自殺性死亡的基因，還有TRIF-PKR訊息傳遞如何引發自殺性死亡和干擾素反應。我們預期對於巨噬細胞的活化和自殺性死亡之間的連結能夠有一個更清楚的藍圖。本研究成果對於治療發炎及感染性疾病將會提供新的研究視野，促進新的醫療方法產生。<br> Abstract: The innate immune system recognizes invading pathogens resulting in the activation of a host defense response. Macrophages play a central role in innate immunity both by their ability to detect pathogens and alert other cells to their presence, and by their ability to destroy foreign organisms. Therefore, macrophages are the prime targets of many intruders. Several bacterial pathogens such as Bacillus anthracis escape detection and destruction by inducing macrophages to undergo apoptosis. Furthermore, defective apoptosis in macrophages can result in chronic as well as acute inflammatory disease. Unfortunately, the mechanism by which macrophage apoptosis is regulated remains elusive. By studying how B. anthracis induces apoptosis in activated macrophages, we found that activation of two signaling pathways, p38 MAPKs and NF-B are necessary for the prevention of bacteria-induced apoptosis of macrophages, and that the dsRNA responsive protein kinase PKR is a critical mediator of pathogen-induced macrophage apoptosis. Based on the critical role of TLRs in activation of macrophages and their effector functions, this proposal will focus on understanding how apoptosis can be suppressed or triggered in activated macrophages in response to TLR4 receptor activation by elucidating the mechanisms by which both NF-kB and p38 contribute to the induction of anti-apoptotic genes and how TRIF-PKR signaling pathway mediates apoptotic and interferon-inducing pathways. The knowledge generated from this project would have important implications in the understanding and therapy of certain inflammatory and infectious diseases.先天性免疫系統Innate Immunity