Dr. Lee, Eminy H.Y. 李小媛 博士

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Dr. Lee, Eminy H.Y.
李小媛 博士

Distinguished Research Fellow
特聘研究員

Specialty:
  • Learning and Memory
  • Neuroprotection against  Alzheimer's Disease
  • Rett Syndrome

RESEARCH

One of our research interests is to study the cellular 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. We have earlier identified the protein inhibitor of activated STAT1 (pias1) gene, a gene involved in inflammation and innate immune response, plays an important role in facilitating spatial memory formation in rats. Because PIAS1 also functions as a SUMO E3 ligase, we further demonstrated that PIAS1 facilitates memory formation through enhanced SUMOylation of STAT1 and CREB in rat hippocampus. Role and mechanism of other novel candidate genes that regulate memory formation is currently under investigation.

In addition, we are interested in the neuroprotection mechanisms against Alzheimer’s disease (AD). We have earlier identified a novel signaling pathway that functions as an endogenous defense mechanism upon amyloid-beta insult. In brief, we have found that acute amyloid-beta induces the activation of protein kinase SGK. SGK directly phosphorylates STAT1 and STAT2 that results in increased expression of the anti-apoptotic gene Mcl-1. Activation of SGK also reduces amyloid-beta induced plaque formation in rat hippocampus. On the other hand, epigenetic regulation plays an important role in various biological functions and dysregulation of protein SUMOylation is suggested to be involved in the pathogenesis of AD. Our recent study focused on epigenetic regulation of protein SUMOylation in protection against amyloid-beta toxicity using animal model of AD.

We are also interested in the mechanism of Rett syndrome (RTT). RTT is caused by mutations of the MECP2 gene. We have recently found that several MECP2 mutations identified in RTT patients show decreased level of MeCP2 SUMOylation. On the other hand, increased MeCP2 SUMOylation by PIAS1 enhances Bdnf gene expression and rescues the behavioral and synaptic deficits in a mouse model of RTT. IGF-1 that has a therapeutic effect in RTT patients also increases MeCP2 SUMOylation. Further studies are undertaken to examine other molecular mechanisms underlying RTT and the therapeutic strategies alleviating the symptoms in RTT patients.

研究介紹

我們實驗室的研究興趣之一是探討哺乳動物長期記憶形成的細胞及分子生物機制。在確認了一個新穎的重要基因之後,我們進一步研究它的基因表現、訊息傳遞及其參與在記憶形成的調控機制。我們先前發現一個在發炎與免疫反應中扮演重要角色的基因pias1, 也會明顯促進大鼠空間記憶的形成。因為PIASI 同時也是一個類小泛素化的E3連接酶,我們後續的實驗進一步證實了 PIASI 促進記憶是透過增加海馬廻中STAT1和CREB的類小泛素化而逹成。其它會調控記憶的新穎及重要基因以及這些基因影響記憶形成的機制也正在探討中。

此外,我們也探討阿茲海默症的神經保護機制。我們先前的研究曾確認了一條內生性的、新穎的訊息傳遞途徑可抵抗急性貝它類澱粉蛋白所產生的毒性。我們發現貝它類澱粉蛋白會活化SGK蛋白激酶。SGK的活化會進一步磷酸化STAT1及STAT2進而促進抗淍亡基因Mcl-1的表現。此外,SGK的活化也會減少貝它類澱粉蛋白在大鼠海馬廻中所產生的斑瑰。表觀遺傳學調控在許多細胞功能上都扮演重要的角色,而蛋白類小泛素化的調控異常也被認為和阿茲海默症的病理有關。我們近期的研究即是利用阿茲海默症的小鼠模式探討蛋白類小泛素化的表觀遺傳學調控在保護神經細胞對抗貝它類澱粉蛋白毒性的分子生物機制。

近年來,我們也對雷特氏症的研究有興趣。雷特氏症主要是因為MECP2此基因的突變所造成。我們最近的研究發現,在雷特氏症患者身上確認到的數個MECP2基因發生突變的位點都有MeCP2蛋白類小泛素化明顯減少的現象。而PIASI會增加MeCP2蛋白的類小泛素化,並促進Bdnf 的基因表現,同時也可挽救雷特氏症模式小鼠的行為與突觸缺陷。IGF-1在臨床上被認為對雷特氏症患者有療效,我們發現IGF-1也會顯著促進MeCP2蛋白類小泛素化的程度。目前的研究正在繼續探討雷特氏症的其它分子生物機制以及減緩雷特氏症候群的治療策略。

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