雖然 microRNA (miRNA) 療法充滿應用潛力，然而高分子 miRNA 傳遞系統仍然有很大改善空間，其中最關鍵為釐清高分子載體之分子細胞參與作用機轉，並能合理化去調控細胞自生分子作用訊息。故本計劃的主要目的為、透過生物資訊工具有系統的設計、來建構一個有功能性的陽離子性高分子 miRNA傳遞系統，而能廣泛應用於未來臨床核酸治療之開發。我們將選定具有誘導細胞自我吞噬之 miRNA 作為研究重點。本計畫第一年將利用生物晶片來探討陽離子性高分子/miRNA傳遞系統之全面誘導細胞自我吞噬miRNA表現情形，以了解陽離子性高分子調控目標細胞自我吞噬之 miRNA 之表現及評估高分子載体引發相關 "Off-target" 效應。第二年將進一步了解當調控細胞之細胞自我吞噬作用時，會如何影響陽離子性高分子 miRNA 表現效率與細胞自我吞噬與細胞凋亡相互之交叉分子作用。第三年將追跡陽離子性高分子誘導細胞自我吞噬之 miRNA 傳送系統之細胞內交流，來確認陽離子性高分子載體之傳送路徑。透過此研究，我們將更能理性化設計一個更有效率及安全之陽離子性高分子 miRNA 傳送系統。 Despite of great potentials of the applications of microRNA therapy, there are still much room to improve on the polymeric microRNA delivery systems. Among these improvements, the most crucial point is to clarify the involved cellular molecular mechanisms of polymer vectors and further rationally regulate the signals of the molecular interactions in cells by polymer vectors. Therefore, the aim of this study is to construct the functional polycation microRNA systems via tools of bioinformatics for the future clinical applications of nucleic acid therapy. We will target on the microRNA that can induce autophagy in cells. The first year of the study will explore miRNA global expression profiles on autophagy from polycation microRNA delivery systems by applying microarray analysis for better understanding the influences of expression levels by polymer vectors and its off-target effects. The second year of the study will modulate polyplex-mediated microRNA transfection by the regulators of autophagy and investigate the interactions between autophagy and apoptosis in cells treated with polycation microRNA delivery systems. Finally, the third year of the study will trace the intracellular trafficking of polycation microRNA delivery systems to identify their delivery pathways. Through these investigations, we can rational design more safe and efficient polycation microRNA delivery systems.
