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      化學所在基于cell-SELEX技術的生物標志物發現方面取得系列進展
      2019-04-30 | 編輯:郭杰 | 【 】【打印】【關閉

        發現新的生物標志物和發展新的分子探針,在分子水平上探索生命過程和疾病發生發展機制是現代生物醫學領域前沿研究方向之一。 

        在國家自然科學基金委、科技部和中國科學院的支持下,中科院化學所活體分析化學院重點實驗室上官棣華課題組研究人員長期致力于生物標志物和分子探針的研究。近年來,他們利用Cell-SELEX技術獲得了系列識別特定腫瘤細胞的核酸適配體分子探針Plos One 2014, 9, e100243Biomaterials 2014, 35, 6998 Angew. Chem. Int. Ed. 2016, 55, 3914Talanta 2019, 194, 437,研究了核酸適配體識別機理,建立了新的生物標志物檢測方法Sci. Rep. 2017, 7, 15467ACS Appl Mater Inter 2018, 10, 2312,發展了基于SILAC的定量蛋白質組學技術的核酸適配體蛋白靶標的鑒定方法Mol. Cell. Proteomics 2015, 14, 2692,為基于Cell-SELEX技術的生物標志物發現奠定了基礎。 

        神經突的生長是神經發育的關鍵,識別神經突的分子探針對于評估神經生長發育、藥物的神經毒性和促神經再生作用等是必不可少的。為了獲得神經突探針,王林林博士生和邴濤副研究員等建立了神經突-SELEX方法,并篩選獲得了一個結合神經突的DNA核酸適配體yly12,鑒定yly12的分子靶標為神經細胞粘附分子L1L1CAM),以yly12為分子探針發現L1CAM在多種腫瘤細胞中高表達。他們成功將yly12應用于活細胞之間三維神經突網絡的成像和正常腦組織切片上的神經纖維染色;并發現yly12對細胞間神經突的生長具有一定抑制作用。yly12可作為神經突的分子探針用于神經科學研究J. Am. Chem. Soc. 2018, 140, 18066。目前正在進行L1CAM表達與腫瘤的相關性研究。   

        1 核酸適配體yly12用于三維神經突網絡成像 

        蛋白的二聚化是生物體內一種重要的生理現象,蛋白的二聚體往往是蛋白質發揮生物學功能的重要形式。但是由于難以獲得完整、穩定的蛋白二聚體用于制備分子探針,到目前為止,沒有單一分子探針可以用于細胞或組織上蛋白二聚體的原位檢測,嚴重制約了蛋白二聚體的功能研究。邴濤副研究員和沈璐瑤博士生等利用cell-SELEX技術,首次篩選獲得了特異性識別堿性磷酸酶異源二聚體、而不識別單體的核酸適配體BG2。利用該核酸適配體,發現堿性磷酸酶異源二聚體在數種腫瘤細胞上高表達;用核酸適配體成功實現了堿性磷酸酶異源二聚體的分離純化以及荷瘤小鼠中高表達堿性磷酸酶異源二聚體的腫瘤的原位成像。堿性磷酸酶的同工酶廣泛分布在生物體內,但是堿性磷酸酶異源二聚體在組織和細胞中的分布和功能尚未知,核酸適配體BG2可為揭開堿性磷酸酶異源二聚體的奧秘以及腫瘤檢測提供重要分子工具Adv. Sci. 2019, 1900143。目前正在研究堿性磷酸酶異源二聚體作為腫瘤標志物的可行性研究。 

        研究人員在該領域的研究成果,將加速cell-SELEX技術在生物標志物發現領域的廣泛應用,將促進新的生物標志物的發現。 

        

        2 核酸適配體BG2特異性地識別堿性磷酸酶異源二聚體的示意圖及其用于腫瘤原位成像。 

          

        活體分析化學院重點實驗室 

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