Ph.D. Univ. of California, San Diego
One of our research interests is to study the pathogenesis of and neuroprotection against Alzheimer’s disease (AD). Recently, we have found that galectin-3 promotes neuroinflammation and contributes significantly to the pathogenesis of AD. The expression level of galectin-3 is increased in the hippocampus of APP/PS1 mice at very early stage and could be considered as a biomarker and novel therapeutic target for AD. In studying the neuroprotection against AD, we have found that protein SUMOylation plays an important role in this process. For example, SUMOylation of Elk-1 decreases GADD45α expression and reduces the number of apoptotic neurons in the hippocampus of APP/PS1 mice. SUMOylation of AICD increases AICD nuclear translocation, increases the expression of neprilysin and transthyretin and enhances amyloid-beta degradation in APP/PS1 mice. We are currently examining the neuroprotective role and molecular mechanism of APP SUMOylation. We also aim at identifying endogenous stimuli that induce APP SUMOylation. Moreover, we are exploring other endogenous protection mechanisms against AD. These results together should provide novel insights and therapeutic strategies against AD.
In addition, we are also interested in studying the neural and molecular mechanisms of mammalian long-term memory formation. Upon identification of a novel candidate gene, we further study the expression, signaling pathway and regulation mechanism of this gene involved in memory formation. By using the differential display PCR (DD-PCR) strategy, we have previously identified the serum- and glucocorticoid-inducible kinase (sgk) gene and the protein inhibitor of activated STAT1 (pias1) gene involved in memory processing. Identification of the sgk gene provides novel molecular mechanism underlying glucocorticoid-induced memory facilitation in humans and animals. Identification of the pias1 gene reveals that protein SUMOylation is a novel and important mechanism underlying long-term memory formation. By using the same DD-PCR strategy, we have recently indentified other candidate genes that play novel roles in regulating long-term memory formation in rats and mice. We are currently investigating the molecular mechanisms underlying these regulations.
我們實驗室的研究興趣之一是探討阿茲海默症的病理成因及其神經保護機制。近期我們發現galectin-3這個醣蛋白會促進神經發炎並且是造成阿茲海默症的重要成因。Galectin-3在海馬迴的表現量在年輕的APP/PS1小鼠就有明顯的增加，因此，galectin-3可能可以做為阿茲海默症的一種生物指標及新穎的治療標的。在探討阿茲海默症的神經保護機制方面，我們發現蛋白質的類小泛素化扮演一個重要的角色。例如：Elk-1的類小泛素化會降低GADD45a 的表現並減少APP/PS1小鼠海馬迴的神經細胞凋亡。AICD的類小泛素化會增加AICD進核的能力，進而增加 neprilysin 及 transthyretin 的表現並促進APP/PS1小鼠腦中類澱粉蛋白的降解。我們目前正在探討APP蛋白類小泛素化的神經保護角色及機制，我們也要確認可以引發APP類小泛素化的內生性刺激以及探索其他的內生性神經保護機制。這些研究結果將使我們對於阿茲海默症的病理成因有嶄新的瞭解及新穎的治療策略。
本實驗室的另一項研究興趣是探討哺乳動物長期記憶形成的神經和分子生物機制。在確認了一個參與記憶形成的候選基因之後，我們會進一步探討其表現量，訊息傳遞途徑以及對記憶的調控機制。先前，利用PCR差異表現法，我們曾經確認了sgk 基因和 pias1 基因在長期記憶形成中的新穎角色和機制。Sgk 基因的確認使科學家對於醣皮質素在人類和動物能促進記憶提供了一個很好的分子生物學上的詮釋。Pias1 基因的確認則揭露了蛋白質的類小泛素化在長期記憶形成中所扮演的重要角色。利用同樣的 PCR 差異表現法策略，我們最近還確認了其他的新穎候選基因，目前我們正在探討這些基因在長期記憶中的角色及其對記憶形成的調控機制。