2020-08-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/666570摘要：脾酪胺酸激&#37238;Spleen tyrosine kinase (Syk)是一種非受體型的酪胺酸激&#37238;，許多研究已證實Syk在許多細胞的生理功能，諸如生長、附著、移動與自戕等皆扮演重要角色，而多種免疫細胞在發育與功能中需要Syk的調控。過去我們研究了Syk在許多種免疫細胞中的功能，綜觀探討Syk的文獻中，對於樹突細胞（dendritic cell, DC）的研究不多，尤其是發育的部分卻沒有任何報告。樹突細胞能啟動後天免疫反應；而除了活化免疫，對於維持免疫耐受也很重要，尤其在腸道中是由一群表現CD103的調節型樹突細胞（regulatory DC, regDC）來調控，當regDC失調時就可能引發發炎或自體免疫疾病。已知在腸道發炎疾病(Inflammatory Bowel Disease, IBD)中，樹突細胞同時扮演了正向與負向調控，可能是由不同的族群來控制。因此我們提出探討Syk在腸道DC發育與功能中的角色，並將利用在DC專一性Syk缺陷小鼠(CD11c△Syk)來進行。本計畫有三個目標：一、檢視Syk缺陷對周圍組織與腸道DC族群發育的影響。令我們驚訝的是，分析所有淋巴結中DC族群時，初步觀察到僅有腸繫膜淋巴結中的CD103+ DC族群在Syk△CD11c小鼠中有改變；二、利用Syk△CD11c小鼠來研究在腸道耐受性模式中Syk對腸道DC的影響。初步結果顯示Syk△CD11c小鼠有較嚴重的腸炎症狀；三、探討Syk在細胞中如何參與調控發育與功能相關的機制。本計畫的完成將首次揭露Syk在腸道CD103+ DC中的角色，並且進一步提出Syk抑制劑在治療免疫疾病與生技發展的應用性。<br> Abstract: Spleen tyrosine kinase (Syk) is a non-receptor protein tyrosine kinase and a lot of studies have identified the immune cell types that require Syk for development and function. In addition, Syk also plays critical roles in various cellular responses, such as proliferation, adhesion, migration, and apoptosis. We have studied the roles of Syk in many types of immune cell in past. However, the regulatory role of Syk in the development of dendritic cells (DCs) have not been well described. DCs initiate adaptive immune responses, but DCs also play a crucial role in maintaining self-tolerance, especially in gut via a group of regulatory CD103+ DC (regDC). Dysfunction of regDC increases the susceptibility to develop inflammatory and autoimmune diseases. Both positive and negative regulations of DCs have been shown in Inflammatory Bowel Disease (IBD), and could be exerted by different DC populations. Thus, we propose to study the role of Syk in the development and function of gut DCs by using DC-specific Syk-deficient mice (CD11c△Syk). There are three specific aims in this proposal. First, we will examine the DC populations in peripheral tissues and gut in CD11c△Syk mice. Surprisingly, our preliminarily showed only the different CD103+ DC composition in mesenteric lymph nodes was observed in CD11c△Syk mice. The second, we will study the effect of Syk on gut DCs by using an oral tolerance model. We have preliminarily found that CD11c△Syk mice have more severe DSS-induced colitis than that in control mice. The third, we will reveal the mechanism of Syk involved in which signaling pathway for the development and function of gut CD103+ DCs. We expect that our study will provide novel information about the role of Syk in gut CD103+ DCs for the first time. Furthermore, the applications of Syk inhibitors in the therapy of immune-related diseases and biotechnology will be suggested.樹突細胞CD103樹突細胞腸道耐受性模式腸道發炎疾病Syk磷酸激&#37238dendritic cell (DC)CD103+ DCoral tolerance modelInflammatory Bowel Disease (IBD)Spleen tyrosine kinase (Syk)