课题基金基金详情
靶向Hsp90-共伴侣蛋白复合物阻断前列腺癌去势抵抗表型转化的机制研究
结题报告
批准号:
82002720
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
张立旻
依托单位:
学科分类:
肿瘤治疗抵抗
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
张立旻
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中文摘要
抑制Hsp90治疗前列腺癌是近年来的前沿热点。申请人前期研究发现靶向Hsp90的共伴侣蛋白可抑制前列腺癌,且比直接抑制Hsp90产生的副作用更小;我们还意外发现协助雄激素受体活化折叠的共伴侣蛋白Hop亦可作为候选靶点,而雄激素受体(AR)活化在前列腺癌发生去势抵抗过程中起关键作用。故推测靶向Hsp90/Hop分子伴侣组能够通过影响AR活化来阻止去势抵抗表型的发生,值得深入研究。但预实验中我们发现,对于雄激素依赖性不同的前列腺癌细胞系,靶向Hsp90/Hop会导致差异化的效果;结合文献复习后推测Hsp90分子伴侣组的异质性可能是其关键原因。故本研究将利用非变性电泳测定不同细胞系和条件下Hsp90等电点,联合蛋白质谱,构建蛋白-蛋白互作网络模型,探索分子伴侣组的异质性,并对其下游调控机制进行探讨;从而明确如何精准靶向Hsp90-共伴侣复合物以阻止前列腺癌发生去势抵抗,为前列腺癌治疗提供新思路。
英文摘要
Inhibition of Hsp90 in the treatment of prostate cancer is the state of art in recent years. Our previous research found that targeting the co-chaperone of Hsp90 can inhibit prostate cancer and has fewer side effects than directly inhibiting Hsp90; we also unexpectedly discovered that the co-chaperone protein Hop, which assists androgen receptor activation and folding, can also be a candidate target. And the activation of AR plays a critical role in the castration resistance of prostate cancer. Therefore, it is speculated that targeting Hsp90 / Hop molecular chaperome can prevent the occurrence of castration resistance phenotype by affecting AR activation, which is worthy of in-depth study. However, the preliminary experiments implied that among prostate cancer cell lines with different androgen dependence, targeting Hsp90 / Hop will induce the differentiated effects; after reviewing the literature, it is speculated that the heterogeneity of the Hsp90 molecular chaperome may be the key reason. Therefore, this study will utilize native electrophoresis to determine the isoelectric point of Hsp90 in different cell lines and conditions, combine mass spectrum of protein profiling, and establish a protein-protein interaction network model, in order to investigate the heterogeneity of the molecular chaperone group, and explore its downstream regulatory mechanism. Finally, we aim to make it clear how to precisely target Hsp90-co-chaperone complex to prevent castration resistance of prostate cancer, and provide new strategy for the treatment of prostate cancer.
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
Prevalence of tumour-infiltrating CD103+ cells identifies therapeutic-sensitive prostate cancer with poor clinical outcome
肿瘤浸润 CD103 细胞的普遍存在可识别临床结果较差的治疗敏感前列腺癌
DOI:10.1038/s41416-023-02183-4
发表时间:2023-02-09
期刊:BRITISH JOURNAL OF CANCER
影响因子:8.8
作者:Zhou, Quan;Ou, Yuxi;Jiang, Haowen
通讯作者:Jiang, Haowen
DOI:10.1080/15592294.2023.2178802
发表时间:2023-12
期刊:EPIGENETICS
影响因子:3.7
作者:Dai, Xiyu;Chen, Xinan;Chen, Wensun;Ou, Yuxi;Chen, Yiling;Wu, Siqi;Zhou, Quan;Yang, Chen;Zhang, Limin;Jiang, Haowen
通讯作者:Jiang, Haowen
国内基金
海外基金