糖鏈受體在腫瘤微環境中的功能機制研究

顧建新+阮元元

摘 要：糖鏈是繼蛋白質、核酸之后的第三條生命之鏈。研究表明，正常細胞表面超過70%的蛋白被糖基化修飾。在腫瘤中，糖基化的改變及糖鏈異常是一種非常普遍的現象，糖鏈異常在腫瘤增殖、遷移、侵襲、免疫逃避和耐藥等過程中起重要作用。因此闡明糖鏈結構及其受體在腫瘤發生發展過程中的作用，有助于在此基礎上尋找腫瘤的治療靶點以及進行基于糖類的創新藥物研究，這是當今國際上生命科學研究中最受關注的領域之一。腫瘤是一個嚴重的公共衛生問題，開辟腫瘤診斷和治療的新理念和新策略是一項十分迫切的國家需求。該項目旨在通過糖化學與糖生物學兩大學科的交叉和整合，以我國發病率較高的肺癌、肝癌、乳腺癌和宮頸癌為主要研究對象，從糖科學的新視角探索糖鏈在腫瘤發生、發展和轉移過程中的功能及分子機制；采用糖化學生物學方法，擬解決兩個關鍵科學問題：①腫瘤功能相關糖鏈探針的可獲得性問題；②腫瘤相關糖鏈的變化規律和功能機制。該項目主要研究內容將緊緊圍繞當前糖化學生物學發展中的若干重要前沿問題，從腫瘤細胞和腫瘤微環境兩個方向，從糖鏈結構特征、糖鏈合成調控和糖鏈功能實現等方面入手，運用糖鏈探針研究腫瘤相關特征性糖鏈結構、其調控機制及其功能性凝集素受體，揭示糖鏈在腫瘤發生、發展和轉移中的生物學功能和分子機制，發現腫瘤中糖鏈相關的診斷和治療靶點。另一方面，以解決糖鏈的高效合成為導向，采用化學及酶法兩條互補的途徑合成腫瘤相關的糖鏈及其綴合物分子，并以此為探針來驗證特異性糖鏈在腫瘤生物學功能中的作用；進一步設計合成糖鏈及其模擬物，對腫瘤的糖鏈異常進行干預和調控，發展新的腫瘤治療手段。

關鍵詞：糖化學 糖生物學 腫瘤 糖鏈探針 糖基轉移酶 凝集素

Abstract：Sugar chain is the third chain of life ，following protein and nucleic acid.Studies show that more than 70% of the normal cell surface proteinsare modified with glycosylation. In tumors， abnormal changes of glycosylation and sugar chain are common phenomenons.Abnormity of sugar chain plays an important role in tumor proliferation， migration， invasion， immune escape and chemoresistance.As a result ， clarifying sugar chain structure and the function of its receptors in the development of tumors will contribute to find tumor therapeutic targets and do innovative drug research.This is one of the most popular areas of scientific research nowadays. Tumor is a serious public health problem. Opening up new ideas of the tumor diagnosis and treatment is a very pressing needs for a country.With the crossover and integration of chemical and biological sugar，this project aims to explore the function and molecular mechanism of the sugar chain in the process of tumorigenesis， development and metastasis， on the basis of higher incidence of lung cancer， liver cancer， breast cancer and cervical cancer in our country as the main research object. Sugar chemical biology method is used to solve two key scientific problems：① The availability of sugar chain probe about tumor function；②The changes of the sugar chain and functional mechanism related to tumor. The main research of this project will closely involve the current important frontier issues in the development of chemical biology， from both tumor cells and tumor microenvironment aspects.We will also use sugar chain probe to explore tumor related sugar chain structure， its regulatory mechanism and functional lectin receptors， evealing the sugar chain in the occurrence， development and metastasis of tumor biology function and molecular mechanism of tumours in the sugar chain related diagnostic and therapeutic targets. On the other hand， in order to solve the efficiency of the synthesis of sugar chain， two complementary ways of using chemical and enzymatic synthesis will be used to synthesize the tumor associated sugar chain and its conjugated molecules.In this way，we can find a probe to verify the special role of sugar chain in tumor biology and further design synthetic sugar chain and its simulation.This will contribute to the intervention of tumor related abnormal regulation of sugar chain and develop new tumor treatment.

Key Words：Glycochemistry； Glycobiology； Tumor； Glycan probe； Glycosyltransferase； Lectin

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