Regulatory Role of Mitochondrial DNA in Bladder Cancer Progression

线粒体 DNA 在膀胱癌进展中的调节作用

基本信息

  • 批准号:
    10575847
  • 负责人:
  • 金额:
    $ 21.74万
  • 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:
    2023-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Bladder cancer (BCa) is a common solid tumor and exhibits poor outcomes when regionally advanced or metastatic. Only modest improvements are seen even with aggressive surgical or medical treatments. Most patients with advanced cancer ultimately succumb to their disease with the most significant prognostic factor being the presence of metastasis. While much work has been done on identifying the presence of metastatic tumor cells in lymph nodes, little research currently explores the mechanisms that govern BCa progression to a metastatic phenotype. It is now well recognized that genetic factors, intrinsic to the primary tumor, and microenvironmental factors, independent of the primary tumor are involved in metastatic progression. One key understudied regulator of metastatic efficiency may be mitochondrial DNA (mtDNA). Variations in mitochondrial copy number and loss of mtDNA have been implicated as pathogenic events in BCa, and changes in mtDNA have been measured in patient samples; however, little is understood about the functional contribution of mtDNA to metastatic progression due to lack of suitable and available laboratory models. We have developed a model to determine contributions of mtDNA, designated MNX – mitochondrial-nuclear exchange. Transgenic mice are generated with matched nuclear DNA but different mtDNA from separate strains such that maternal inheritance determines mtDNA content in constant nuclear backgrounds. Prior studies from the Welch lab (mPI) using these mice in breast and melanoma models indicate mtDNA is a novel metastasis efficiency regulator. Moreover, mtDNA changes in the microenvironment independent of the tumor itself may further regulate the potential for metastasis. However, no such studies have been done in genetically credentialed models that accurately recapitulate human disease. Our preliminary data indicates that transfer of C3H/HeN mtDNA into a C57Bl/6J nuclear background results in more rapid tumor progression, especially in female mice. We hypothesize that specifically altering mitochondrial genetics will fundamentally alter tumor progression and metastasis rates in BCa via signaling changes in both tumor cells and the tumor stroma. We will use the highly credentialed N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) induced BCa model in murine strains with different rates of tumor formation (C3H/HeN and C57BL/6J) to investigate this hypothesis. In Specific Aim 1, we will evaluate the role of mtDNA in primary BCa tumor progression to metastasis using WT and MNX mice. In Specific Aim 2, we will determine the contribution of cellular and stromal elements to BCa metastasis in WT and MNX mice. These studies will define the role of mtDNA in this model and lead to future experiments understanding how loss or gain of mtDNA specifically effects both murine laboratory models and patients.
摘要

项目成果

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JOHN A TAYLOR其他文献

JOHN A TAYLOR的其他文献

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{{ truncateString('JOHN A TAYLOR', 18)}}的其他基金

Drug Discovery, Delivery, & Experimental Therapeutics Research Program
药物发现、交付、
  • 批准号:
    9975745
  • 财政年份:
    2012
  • 资助金额:
    $ 21.74万
  • 项目类别:
Drug Discovery, Delivery, & Experimental Therapeutics Research Program
药物发现、交付、
  • 批准号:
    9750043
  • 财政年份:
  • 资助金额:
    $ 21.74万
  • 项目类别:

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