Defining the mutational pathogenesis of oral preneoplasia

定义口腔癌前病变的突变发病机制

基本信息

  • 批准号:
    10380083
  • 负责人:
  • 金额:
    $ 56.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-15 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

Project Summary: Oral potentially preneoplastic diseases are common with worldwide prevalence of approximately 4%, and millions of cases in the United States alone. A large subset of these harbor the histopathological features of oral dysplasia, the lesions most likely to progress to oral squamous cell carcinoma. Despite years of research on these lesions, the approach to management of these lesions is quite variable. In particular, because we lack a clear molecular classification of these lesions, we do not have good, clinically applicable biomarkers that predict which lesions are likely to progress to cancer (and therefore require treatment) and which are likely to not progress (and therefore can be observed). Further, we lack a full understanding of the identity of the mutations responsible for reprogramming cells from normal oral keratinocytes into dysplastic oral keratinocytes, and subsequently to carcinoma cells. We also do not understand how these mutations interact in order to give rise to dysplasia, or how this knowledge could be harnessed to generate novel therapeutic approaches to oral dysplasia. The work proposed within this grant aims to address these questions. First, we will perform next generation sequencing on a large panel of oral dysplasias in order to define the mutational landscape of oral dysplasias in general. Next, we propose performing next generation sequencing on biopsies from a group of patients followed longitudinally over the arc of years whose oral dysplasias ultimately progressed to cancer. We next take advantage of novel gene editing systems in primary human oral keratinocytes combined with optimized organotypic model systems to generate “designer” oral dysplastic lesions and validate the causative mutational events in these lesions. Finally, we leverage our optimized organotypic model systems to predict a precision medicine approach using FDA-approved medications. Once complete, this work will serve as the foundational data resource for the oral dysplasia research community, and will introduce novel, flexible, and powerful model systems to address key questions in oral preneoplastic progression.
项目总结: 口腔潜在癌前疾病很常见,全球患病率约为4%, 仅在美国就有数百万起案件。其中的一大部分具有组织病理学特征 在口腔异型增生中,病变最有可能进展为口腔鳞癌。尽管多年来 对于这些病变的研究,处理这些病变的方法是非常不同的。特别是, 由于我们缺乏对这些病变的明确的分子分类,我们没有良好的、临床适用的 预测哪些病变可能进展为癌症(因此需要治疗)的生物标记物 很可能不会进展(因此可以观察到)。此外,我们还缺乏对 负责将细胞从正常口腔角质形成细胞重新编程为发育不良口腔细胞的突变 角质形成细胞,然后是癌细胞。我们也不知道这些突变是如何相互作用的 为了引起发育不良,或者如何利用这种知识来产生新的治疗方法 口腔发育不良的治疗方法。这笔赠款中提议的工作旨在解决这些问题。首先,我们 将对一大批口腔发育不良患者进行下一代测序,以确定突变 口腔发育不良的总体景观。接下来,我们建议对活检组织进行下一代测序 从一组患者纵向跟踪多年,他们的口腔发育不良最终 发展成癌症。接下来,我们将利用人类初级口腔中的新基因编辑系统 角质形成细胞与优化的器官型模型系统相结合产生“设计型”口腔发育不良 并验证这些病变中的致病突变事件。最后,我们利用我们优化的 器官模型系统,以预测使用FDA批准的药物的精确医学方法。一次 完成后,这项工作将成为口腔发育不良研究社区的基础数据来源,以及 将引入新颖、灵活和强大的模型系统来解决口腔癌前病变的关键问题 进步。

项目成果

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Aaron Tward其他文献

Aaron Tward的其他文献

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{{ truncateString('Aaron Tward', 18)}}的其他基金

Defining the mutational pathogenesis of oral preneoplasia
定义口腔癌前病变的突变发病机制
  • 批准号:
    10681505
  • 财政年份:
    2022
  • 资助金额:
    $ 56.69万
  • 项目类别:
Defining the mutational pathogenesis of oral preneoplasia
定义口腔癌前病变的突变发病机制
  • 批准号:
    10217102
  • 财政年份:
    2020
  • 资助金额:
    $ 56.69万
  • 项目类别:
Tympanic membrane progenitor cells in homeostasis in injury
鼓膜祖细胞在损伤中的稳态
  • 批准号:
    10378139
  • 财政年份:
    2020
  • 资助金额:
    $ 56.69万
  • 项目类别:
Tympanic membrane progenitor cells in homeostasis in injury
鼓膜祖细胞在损伤中的稳态
  • 批准号:
    9973797
  • 财政年份:
    2020
  • 资助金额:
    $ 56.69万
  • 项目类别:
Defining the mutational pathogenesis of oral preneoplasia
定义口腔癌前病变的突变发病机制
  • 批准号:
    10819716
  • 财政年份:
    2020
  • 资助金额:
    $ 56.69万
  • 项目类别:
Defining the mutational pathogenesis of oral preneoplasia
定义口腔癌前病变的突变发病机制
  • 批准号:
    10037424
  • 财政年份:
    2020
  • 资助金额:
    $ 56.69万
  • 项目类别:
Tympanic membrane progenitor cells in homeostasis in injury
鼓膜祖细胞在损伤中的稳态
  • 批准号:
    10599161
  • 财政年份:
    2020
  • 资助金额:
    $ 56.69万
  • 项目类别:
Defining the mutational pathogenesis of oral preneoplasia
定义口腔癌前病变的突变发病机制
  • 批准号:
    10614397
  • 财政年份:
    2020
  • 资助金额:
    $ 56.69万
  • 项目类别:

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