Heatr1调控胰腺癌吉西他滨增敏机制的研究

Using Gemcitabine as the first-line drug or combined with other therapeutic agent to treat pancreatic cancer is not efficient and sometimes even resistant, thus to find a new chemosensitive and prognostic marker is vital. According to a GWAS study by Mayo clinic in 2009, the mutation of Heatr1(HEAT repeat-containing protein 1) gene was associated with the sensitivity to gemcitabine. Besides, our team found Heatr1 could enhance the sensitivity of gemcitabine by promoting the dephosphorylation of AKT-308 while the specific target gene of Heatr1 is still unknown. We will compare the differentially expressed genes in both gemcitabine sensitive and insensitive pancreatic cancer cell lines, confirm the common genes，implement the screening proliferation assay using HCS method to confirm the regulation target of Heatr1. We will implement our research from cell,animal and pancreatic cancer specimen as to discover a novel therapeutic target and improve the chemosensitivity of the pancreatic cancer.

胰腺癌缺乏典型的临床表现，早期诊断困难。即使接受根治切除的患者，5年生存率不到20%.吉西他滨到目前为止仍是胰腺癌的一线化疗药物，但单药或联合用药均未能提高疗效.美国Mayo Clinic一项药物敏感性全基因组关联性分析（GWAS）显示，Heatr1（HEAT repeat-containing protein 1）的突变与吉西他滨的敏感性有相关性；本研究团队也发现Heatr1通过调节AKT-Thr308的去磷酸化而增加了吉西他滨的敏感性；但Heatr1影响吉西他滨增敏的具体基因靶点仍需进行深入研究。本实验方案拟利用基因芯片做吉西他滨敏感株和不敏感株中基因的表达差异情况，寻找共同差异基因，并通过采用高内涵筛选 的增殖功能筛选实验，从mRNA的角度研究HEATR1影响吉西他滨增敏的确切调控靶点，从动物实验、人体标本加以验证，寻找新的增加吉西他滨化疗敏感性的治疗靶点。

胰腺癌缺乏典型的临床表现，早期诊断困难。即使接受根治切除的患者，5年生存率不到20%.吉西他滨到目前为止仍是胰腺癌的一线化疗药物，但单药或联合用药均未能提高疗效.美国Mayo Clinic一项药物敏感性全基因组关联性分析（GWAS）显示，Heatr1（HEAT repeat-containing protein 1）的突变与吉西他滨的敏感性有相关性；本研究团队也发现Heatr1通过调节AKT-Thr308的去磷酸化而增加了吉西他滨的敏感性；但Heatr1影响吉西他滨增敏的具体基因靶点仍需进行深入研究。本实验方案利用基因芯片做吉西他滨敏感株和不敏感株中基因的表达差异情况，寻找共同差异基因，并通过采用高内涵筛选 的增殖功能筛选实验，从mRNA的角度研究HEATR1影响吉西他滨增敏的确切调控靶点为ZNF185，并初步发现 Heatr1-ZNF185-SMAD4 通路可能是影响吉西 他滨化疗耐药的通路之一，在预测胰腺癌患者化疗敏感性方面具有较好的临床应用价值。