Epitranscriptomic mechanism of environmental stress response and tumorigenesis

环境应激反应与肿瘤发生的表观转录组机制

基本信息

  • 批准号:
    10642261
  • 负责人:
  • 金额:
    $ 53.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-01 至 2031-05-31
  • 项目状态:
    未结题

项目摘要

Abstract All organisms including humans are constantly exposed to various environmental agents that cause damage to the DNA as well as other biomolecules, and thus threaten genomic integrity and cellular homeostasis, leading to the development of various diseases such as cancer. During the past few years, supported by NIEHS funding, my lab has carried out several screening studies, leading to exciting discoveries on the role of RNA modifications in DNA repair, cellular homeostasis, and tumorigenesis induced by UV irradiation and arsenic, two known carcinogenic agents. These results focus particularly on the most abundant internal mRNA methylation, N6- methyladenosine (m6A) mRNA methylation. However, the major challenge is that how environmental agents interact with the epitranscriptome in disease pathogenesis remains poorly understood. Based on the discoveries made in our published work and our unpublished findings, I propose to test this overarching hypothesis: environmental insults dysregulate the epitranscriptomic machinery and thus impair genomic integrity and cellular homeostasis, leading to tumorigenesis. The focus of my R35 application is to determine the epitranscriptomic mechanism of environmental stress response and tumorigenesis in biochemical systems, cells, and mouse xenograft/orthotopic/genetic tumor models. As the research program evolves, we will then establish the relevance of these discoveries in human samples. Furthermore, we will also expand our investigation to explore how RNA modifications are modulated by other environmental carcinogenic agents, in skin cells and in epithelial cells of other tissue origins that are targeted by these carcinogens. We will employ the novel m6A methylome sequencing technology developed by our collaborator’s lab, as well as other sequencing technologies to map the environmental epitranscriptome. In addition, we will continue to create new genetic mouse models to investigate the role of RNA modifications in environmental tumorigenesis. My broad research program will pursue the following goals: (i) establish the mechanism by which m6A RNA methylation regulates tumorigenesis following UVB radiation and arsenic exposure; (ii) discover new enzymes that regulate m6A mRNA methylation in environmental stress response and tumorigenesis; (iii) explore the roles of other RNA modifications in environmental stress response and tumorigenesis; and (iv) identify new molecules that modulate RNA modifications as probes/therapeutics. The resultant discoveries can vastly expand our knowledge to further establish the role of environmental epitranscriptomics in stress response and cancer, and open up new opportunities to develop new epitranscriptomics-based probes/therapeutics to improve prevention and therapy for cancer as well as other diseases.
摘要 包括人类在内的所有生物体都不断地暴露在各种环境因子中, DNA以及其他生物分子,从而威胁到基因组的完整性和细胞内稳态, 与癌症等多种疾病的发展密切相关。在过去的几年里,在NIEHS基金的支持下, 我的实验室已经进行了几项筛选研究,导致了关于RNA修饰作用的令人兴奋的发现。 在DNA修复、细胞内稳态和由UV照射和砷诱导的肿瘤发生中,两种已知的 致癌物质这些结果特别集中在最丰富的内部mRNA甲基化,N6- 甲基腺苷(m6A)mRNA甲基化。然而,最大的挑战是环境因素如何 在疾病发病机制中与表转录组相互作用的机制仍然知之甚少。基于这些发现 在我们发表的工作和我们未发表的发现中,我建议测试这个总体假设: 环境损伤使表转录组机制失调,从而损害基因组的完整性和细胞 体内平衡,导致肿瘤发生。我的R35应用程序的重点是确定 生化系统、细胞和小鼠的环境应激反应和肿瘤发生机制 异种移植/原位/遗传肿瘤模型。随着研究计划的发展,我们将建立 这些发现在人类样本中的相关性。此外,我们亦会扩大调查范围, 皮肤细胞和上皮细胞中其他环境致癌物质如何调节RNA修饰 这些致癌物所针对的其他组织来源的细胞。我们将使用新的m6A甲基化组 我们合作者实验室开发的测序技术,以及其他测序技术, 环境表型组。此外,我们将继续创造新的遗传小鼠模型, 研究RNA修饰在环境肿瘤发生中的作用。我的广泛研究计划将追求 以下目标:(i)建立m6A RNA甲基化调控肿瘤发生的机制 UVB辐射和砷暴露后;(ii)发现调节m6A mRNA甲基化的新酶 在环境应激反应和肿瘤发生中的作用;(iii)探索其他RNA修饰在 环境应激反应和肿瘤发生;以及(iv)鉴定调节RNA的新分子 修饰作为探针/治疗剂。由此产生的发现可以极大地扩展我们的知识, 建立环境表观转录组学在应激反应和癌症中的作用,并开辟新的 开发新的基于表观转录组学的探针/治疗剂以改善预防和治疗的机会 治疗癌症和其他疾病。

项目成果

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Yu-Ying He其他文献

Yu-Ying He的其他文献

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{{ truncateString('Yu-Ying He', 18)}}的其他基金

FTO and RNA methylation in arsenic tumorigenicity
FTO 和 RNA 甲基化在砷致瘤性中的作用
  • 批准号:
    10256609
  • 财政年份:
    2020
  • 资助金额:
    $ 53.39万
  • 项目类别:
FTO and RNA methylation in arsenic tumorigenicity
FTO 和 RNA 甲基化在砷致瘤性中的作用
  • 批准号:
    10454271
  • 财政年份:
    2020
  • 资助金额:
    $ 53.39万
  • 项目类别:
The mechanistic role of METTL14 in UVB-induced skin tumorigenesis
METTL14在UVB诱导的皮肤肿瘤发生中的机制作用
  • 批准号:
    10541839
  • 财政年份:
    2019
  • 资助金额:
    $ 53.39万
  • 项目类别:
The mechanistic role of METTL14 in UVB-induced skin tumorigenesis
METTL14在UVB诱导的皮肤肿瘤发生中的机制作用
  • 批准号:
    9904648
  • 财政年份:
    2019
  • 资助金额:
    $ 53.39万
  • 项目类别:
The mechanistic role of METTL14 in UVB-induced skin tumorigenesis
METTL14在UVB诱导的皮肤肿瘤发生中的机制作用
  • 批准号:
    9751010
  • 财政年份:
    2019
  • 资助金额:
    $ 53.39万
  • 项目类别:
The mechanistic role of METTL14 in UVB-induced skin tumorigenesis
METTL14在UVB诱导的皮肤肿瘤发生中的机制作用
  • 批准号:
    10320925
  • 财政年份:
    2019
  • 资助金额:
    $ 53.39万
  • 项目类别:
Autophagy and GG-NER in UVB-induced skin cancer
UVB 诱导的皮肤癌中的自噬和 GG-NER
  • 批准号:
    8887808
  • 财政年份:
    2015
  • 资助金额:
    $ 53.39万
  • 项目类别:
YTHDF2 and UVB damage response in skin cancer
皮肤癌中的 YTHDF2 和 UVB 损伤反应
  • 批准号:
    10404014
  • 财政年份:
    2015
  • 资助金额:
    $ 53.39万
  • 项目类别:
YTHDF2 and UVB damage response in skin cancer
皮肤癌中的 YTHDF2 和 UVB 损伤反应
  • 批准号:
    10614617
  • 财政年份:
    2015
  • 资助金额:
    $ 53.39万
  • 项目类别:
YTHDF2 and UVB damage response in skin cancer
皮肤癌中的 YTHDF2 和 UVB 损伤反应
  • 批准号:
    10210395
  • 财政年份:
    2015
  • 资助金额:
    $ 53.39万
  • 项目类别:

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城市西班牙裔/拉丁裔青年的执行功能:童年时期接触砷和农药的混合物
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铁转化过程中环境中砷和铀的迁移
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开发砷污染地下水净化技术确保湄公河三角洲水资源安全
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父亲砷暴露的代际和跨代影响
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