探索鞘脂及內源性大麻素在細胞自噬及神經退化性疾病中所扮演的角色
Deciphering the role of lipid mediators in autophagy and neurodegeneration
計畫主持人：臺大生理所-詹智強、中研院生化所-楊維元
Lipid mediators are a class of bioactive lipids involved in many physiological processes, and their dysregulations have been often linked to various diseases such as inflammation, cancer and neurodegeneration. In our current studies, we investigated the role of endocannabinoid system （ECS） in the regulation of autophagy and gut homeostasis as well as sphingolipid homeostasis in neurodegenerative disorders. The ECS, a widespread neuromodulatory system, is composed of endocannabinoid lipid mediators such as anandamide (AEA), 2-arachidonoyl glycerol (2-AG) and their receptors. Our results showed modulation of ECS signaling such as depletion of the signaling terminator, FAAH, caused an accumulation of autophagosomes in larval fat body cells and impaired DSS-induced intestinal stem cell proliferation in adult Drosophila. Another pivotal lipid mediator, sphingolipid, constitutes a family of bioactive lipids, including sphingosine, ceramide, sphingosine-1-phosphate. Sphingolipids have also been implicated in neurodegenerative processes. To decipher the biochemical mechanisms by which sphingolipid enzymes and their products are specifically regulated in CNS, we developed a toolset for labeling endogenous sphingolipid gene and protein expression simultaneously in fly brains. Our results found some candidates for imbalances in gene expression under neurodegerative circustances. However, it remains unclear that how sphingolipid homeostasis changes influence the functioning of the brains under neurodegeneration. We are continuing to study the relevance of these lipid mediators to autophagy and neurodegeneration. By elucidating the mechanisms of how lipid mediators are regulated in fly models , we may develop new therapeutic approaches to Inflammatory and neurological diseases.
脂質調節物質是一類參與許多生理過程的生物活性脂質，其失調常與發炎、癌症和神經退化性疾病有關。在我們目前的研究中，我們調查了內源性大麻素系統 (ECS) 在調節自噬作用和腸道穩態的關係以及神經脂質的恆定在神經退化性疾病中的作用。ECS是一種廣泛存在的神經調節系統，由內源性大麻素脂質調節物質組成，例如花生四烯酸 (AEA)、2-花生四烯酸甘油 (2-AG) 及其受體。我們的研究結果表明，ECS信號的調節，例如喪失信號終結者FAAH會導致自噬體在幼蟲脂肪體細胞中堆積，並使成年果蠅對抗DSS所誘導之腸道幹細胞增殖作用能力受損。而另一種關鍵的脂質調節物質—神經脂質，包括神經鞘氨醇、神經醯胺、神經鞘氨醇-1-磷酸。神經脂質也與神經退化性病程有關。為了解開神經脂質代謝酵素及其產物在中樞神經系統中是如何調控的生化機制，我們開發報導基因果蠅株，用於同時標記果蠅大腦中的內源性神經脂質基因和蛋白的表達。我們的研究找到了一些在神經退化情況下基因表達失衡的候選者。 然而目前尚不清楚神經脂質的恆定狀態是如何影響神經退化中的大腦的功能。我們正持續研究這些脂質調節物質與自噬作用和神經退化的相關性。透過闡明脂質調節物質在果蠅模型中的調節機制，將可能開發出針對炎症和神經系統疾病的新治療方法。
