2019-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/674409摘要：光滑念珠菌（Candida glabrata）為一伺機性人體病原真菌，經常感染免疫力低弱 的病人，例如愛滋病、癌症及器官移植患者。光滑念珠菌可引發念珠菌血症 (candidemia）且具較低的藥物敏感性，感染時若無適當的治療，常可導致近50%的 病患死亡率。目前常用來治療光滑念珠菌感染的藥物仍侷限於三類，包含azoles、 polyenes及echinocandins。雖然新型的azoles及微脂劑型的amphotericin B提供 更多抗真菌藥物選擇，仍難以克服光滑念珠菌的抗藥性。因此，研究光滑念珠菌的 藥物耐受性及毒力能擴展我們對其與寄主交互作用的知識，並且協助發展更佳的治 療方法。SAGA複合體（complex）的乙醯化組件（acetylation module）在真核生 物中具保守性，其包含三個核心蛋白質Gcn5、Ada2及Ada3。研究指出在致病性真菌 中這個複合體可調控與藥物耐受性及毒力相關基因之表現。本實驗室的初步研究成 果發現，若將光滑念珠菌SAGA複合體之轉錄輔助因子Ada2敲除，不僅使ada2突變株 對藥物更加敏感，且特別的是會使毒力上升，這與其他致病真菌ADA2基因敲除株表 現之毒力減弱迥異。因此我們假設SAGA 複合體中其他兩個主要蛋白Gcn5、Ada3可 能也會調控藥物耐受性及毒力。為了測試這個假設，本計劃設定三個研究目標。研 究目標一：分析SAGA複合體在光滑念珠菌中的功能。研究目標二：探討SAGA複合體 在藥物耐受性及毒力所扮演的角色及機制。研究目標三：鑑定藉由SAGA複合體所調 控的藥物耐受性及毒力因子。此研究結果將有助於闡明SAGA複合體於光滑念珠菌之 藥物耐受性及毒力所扮演之角色。<br> Abstract: Candida glabrata, an opportunistic human fungal pathogen, is a frequent cause of infection in immunocompromised patients with AIDS, cancer, or organ transplantation. C. glabrata has poor drug susceptibility and frequently causes candidemia, which can result in up to a 50% mortality rate without appropriate treatment. Available antifungal drugs for C. glabrata infections are limited to three classes: azoles, polyenes, and echinocandins. Although the second-generation azoles and liposomal formulation of amphotericin B have expanded the antifungal drug armamentarium, they have not kept pace with the increasing drug resistance profile of C. glabrata. Hence, studies of C. glabrata virulence and drug tolerance will expand the knowledge of host-pathogen interactions and may result in development of better therapeutic strategies. The SAGA complex acetylation module is conserved in the eukaryotic kingdom and contains Gcn5, Ada2, Ada3, and others. Studies have shown that this complex controls gene regulation correlating with virulence and drug tolerance in pathogenic fungi. Our preliminary data show that deletion of the transcription adaptor Ada2 increases antifungal drug susceptibility and virulence in C. glabrata. The enhanced virulence of the Cgada2 mutant is distinct from the attenuated virulence of the ada2 mutant in other fungal pathogens, including Candida albicans and Cryptococcus neoformans. We therefore hypothesize that two other core components of the SAGA complex, Gcn5 and Ada3, may contribute to drug tolerance and virulence suppression in C. glabrata. To test this hypothesis, we propose three aims focused on (1) analysis of the functions of the SAGA complex, (2) investigation of the roles of the SAGA complex in drug tolerance and virulence, and (3) characterization of virulence factors regulated by the SAGA complex. This study will help to define the roles of the SAGA complex in drug tolerance and virulence in C. glabrata.光滑念珠菌SAGA複合體藥物耐受性毒力Candida glabrataSAGA complexdrug tolerancevirulence