Biochemical and Functional Characterization of the Mutagenic Cytidine Deaminase APOBEC3B in the contextof Squamous Cell Lung Carcinoma

鳞状细胞肺癌中突变胞苷脱氨酶 APOBEC3B 的生化和功能表征

基本信息

  • 批准号:
    9235130
  • 负责人:
  • 金额:
    $ 4.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-03-01 至 2019-02-28
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) comprises the vast majority of all lung cancers, which is the leading cause of cancer-related deaths today. Despite this statistic, the availability of targeted therapeutics that effectively modulates the drivers of NSCLC is surprisingly low. Particularly for squamous cell lung carcinoma (SQCLC), a subtype of NSCLC, there are no successful targeted therapies to date, and thus, the identification and validation of molecular targets driving SQCLC are of high demand. The proposed project outlines the biochemical and cell-based investigation of APOBEC3B, a mutagenic cytidine deaminase known to be overexpressed in a wide array of cancers including SQCLC. The goal of this project is to better characterize APOBEC3B as a potential therapeutic target for SQCLC treatment. In understanding the molecular mechanisms of APOBEC3B-induced carcinogenesis, the proposed study aims to 1) biochemically and biophysically investigate APOBEC3B catalysis, nucleic acid binding, and structure, and 2) validate its association with SQCLC using a series of cell-based experiments. In the first aim, using recombinantly expressed and purified full-length APOBEC3B, a series of steady-state enzyme assays, electrophoretic mobility shift assays, and X-ray crystallography will be utilized to understand the biochemical basis of APOBEC3B mutagenic activity. In the second aim, a panel of SQCLC cell lines and normal lung cancer cell lines will be tested using overexpression and RNAi knockdown methodology to validate the association between APOBEC3B expression levels and carcinogenesis, in the context of SQCLC. Together, these aims will converge in understanding the molecular mechanisms of APOBEC3B-induced carcinogenesis and will provide novel insights into the development of targeted therapy strategies for SQCLC.
 描述(由申请人提供):非小细胞肺癌(NSCLC)占所有肺癌的绝大多数,是当今癌症相关死亡的主要原因。尽管有这一统计数据,但有效调节NSCLC驱动因素的靶向治疗剂的可用性令人惊讶地低。特别是对于鳞状细胞肺癌(SQCLC),NSCLC的一种亚型,迄今为止还没有成功的靶向疗法,因此,对驱动SQCLC的分子靶标的鉴定和验证具有很高的需求。拟议的项目概述了APOBEC3B的生物化学和基于细胞的研究,APOBEC3B是一种诱变性胞苷脱氨酶,已知在包括SQCLC在内的多种癌症中过表达。该项目的目标是更好地表征APOBEC3B作为SQCLC治疗的潜在治疗靶点。在了解APOBEC3B诱导的致癌作用的分子机制时,拟议的研究旨在1)从生物化学和生物药理学角度研究APOBEC3B催化、核酸结合和结构,2)使用一系列基于细胞的实验验证其与SQCLC的相关性。在第一个目标中,使用重组表达和纯化的全长APOBEC3B,一系列稳态酶测定,电泳迁移率变动测定和X射线晶体学将被用来了解APOBEC3B致突变活性的生化基础。在第二个目标中,将使用过表达和RNAi敲低方法测试一组SQCLC细胞系和正常肺癌细胞系,以验证在SQCLC背景下APOBEC3B表达水平与致癌作用之间的关联。总之,这些目标将有助于理解APOBEC3B诱导的致癌作用的分子机制,并为SQCLC靶向治疗策略的发展提供新的见解。

项目成果

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