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我们的研究项目“GALNT1介导的Hedgehog信号调控膀胱癌干细胞自我更新机制研究”获得国家自然科学基金重点项目资助

时间 : 2013-01-01


摘要:膀胱癌为泌尿系最常见的恶性肿瘤,其发病机制尚未明了。我们鉴定了两株抗膀胱癌特异性单抗BCMab1BCMab8,能分离膀胱癌干细胞(BCSCs)。前期发现Hedgehog信号在BCSCs中高度活化。还发现BCSCs中高度表达糖基转移酶GALNT1,推断GALNT1介导的糖基化修饰参与Hedgehog信号活化。在此基础上,我们将鉴定BCSCs新的标志物,探明其生物学特征,通过单细胞测序探讨BCSCs的起源问题。探究Hedgehog信号介导膀胱癌干细胞自我更新的调控作用,明确GALNT1介导的SHh糖基化修饰是SHh蛋白活化所必须的,GALNT1介导的Hedgehog信号是膀胱癌干细胞自我更新维持的重要调控机制。鉴定GALNT1的多肽抑制剂,明确对BCSCs自我更新的干预作用。本课题将揭示Hedgehog信号对BCSCs自我更新调控的机理,为干预BCSCs设计抑制自我更新的药物提供理论基础。

Abstract: Bladder cancer is one of the most common malignancies, whose tumorigenesis have not been elucidated. We developed two novel monoclonal antibody BCMab1 and BCMab8, which could separate bladder cancer stem cellsBCSCs.We found that Hedgehog signaling was activated in BCSCs. We also found that glycosyl transferase GALNT1 was highly expressed in BCSCs, which deduced that glycosylation modification mediated by GALNT1 participated in activation of Hedgehog signaling. We will identify the new surface markers in BCSCs, and verify their biological characteristics. Through the single cell sequencing, we will determine the origin of the BCSCs. We will explore the effects of Hedgehog signaling on self-renewal of BCSCs. We will elucidate SHh glycosylation modification mediated by GALNT1 is required for activation of SHh protein, and verify the Hedgehog signaling mediated by GALNT1 plays the most important role in maintaining self-renewal for BCSCs. We will identify the peptide inhibitors of GALNT1 and investigate its intervention effect on self-renewal of BCSCs. Our study will reveal the mechanism of self-renewal for BCSCs regulated by Hedgehog signaling, and provide theoretical foundations for designing drugs, which suppress self-renewal of BCSCs.


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