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|標題:||&Quot;Characterization of Routes of Avian Reovirus Cell Entry and the Roles of Ampk-Mapk P38, Small G Protein and Autophagy in Virus Replication&Quot;
家禽里奧病毒進入宿主細胞之途徑及AMPK-MAPK p38、small G protein及autophagy在病毒複製所扮演之角色
AbstractAvian reovirus (ARV), an important pathogen in poultry, causes arthritis, chronic respiratory disease, and malabsorption syndrome that cause considerable economic losses to the poultry industry. In the past, we have studied ARV-caused diseases, cell cycle regulation by ARV, and ARV-induced apoptosis and its related pathways. Little is known about the exact mechanisms of ARV cell entry. Therefore, to further understand the mechanism of ARV entry, the first part of this project will explore the route of ARV cell entry and the involved signaling pathways. It has been demonstrated that MAPK p38 could be activated in viruses-infected cells. More recently, we discovered for the first time that AMPK could facilitate MAPK p38 signaling that is beneficial for ARV replication. The exact details on how MAPK p38 affects ARV replication remains an interesting issue waiting to be solved. Therefore, the second part of this project is to study how ARV regulates AMPK-p38 MAPK pathway and to study the activation of p38 MAPK in which stage of viral life cycle and the role of AMPK-p38 MAPK pathway in ARV-induced autophagy and virus replication. Recently, we have also demonstrated for the first time that ARV increased the level of phosphorylated eIF2α and eEF2 in a dose-dependent mechanism. Increased levels of phosphorylated eIF2α and eEF2 in ARV-infected cells do not reduce the levels of viral protein. Our preliminary results also show that infection with ARV notably decrease the level of phosphorylated 4E-BP1 in a dose-dependent manner. To further understand how ARV enhances its own replication through what kind of signaling pathways and to elucidate how ARV shut off cellular translation to benefit virus replication, therefore, the third part of this project is to elucidate whether ARV regulates cellular translation through PI3K-AKT-mTOR pathway or related pathways and to further confirm whether cap-dependent translation is required for ARV replication. This project that elucidates the route of virus entry, study the mechanism of enhancement of virus replication by AMPK-p38 MAPK signaling pathway, and understands the regulation of cellular translation by ARV, is a novel and promising study.
中文摘要家禽里奧病毒 (Aian reovirus; ARV) 感染家禽造成多種疾病，包括病毒性關節炎、營養吸收不良症及慢性呼吸道疾病等，造成業者經濟損失。筆者研究團隊過去在病毒造成雞隻病變、病毒調控細胞週期與細胞轉譯及誘發凋亡之機轉有所鑽研。但ARV如何進入宿主細胞之途徑及機制尚不清楚。因此本計畫第一部分擬探討ARV透過何種endocytosis進入細胞及MAPK 38 及samll G protein與 endocytosis之關聯性。雖然已知許多病毒感染細胞後，可活化p38 MAPK，最近筆者研究團隊首次證實ARV可活化AMPK-p38 MAPK pathway以利於病毒本身之複製，但如何協助病毒進入細胞及病毒複製之機轉仍待釐清。為了進一步釐清ARV如何透過AMPK-p38 MAPK pathway來誘發自噬體(autophagy)以促進病毒的複製，本計畫第二部分擬探討AMPK及p38 MAPK在病毒感染早期所扮演之角色及與ARV誘發細胞產生autophagy以促進病毒複製之機序。最近筆者研究團隊證實ARV感染細胞後，其真核啟始因子eIF2α及eEF2的磷酸化隨之增加，但4E-BP1磷酸化則隨病毒MOI的增加其磷酸化程度呈現減少的趨勢，有趣的是病毒蛋白的轉譯卻未隨eIF2α及eEF2 的磷酸化而被抑制。因此本計畫第三部分將釐清ARV如何透過PI3K/AKT/mTOR pathway去調控細胞的轉譯因子及細胞蛋白轉譯。進一步探討ARV關閉細胞蛋白之轉譯是否有利於病毒複製及活化AMPK-p38 MAPK強化病毒本身的複製是否無需cap-dependent轉譯啟始作用。本計畫探討家禽里奧病毒進入細胞途徑及機制、家禽里奧病毒活化AMPK-p38 MAPK pathway及誘發自噬體及調控細胞的轉譯作用以促進病毒本身之複製，是家禽里奧病毒領域之創新研究。
|Appears in Collections:||分子生物學研究所|
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