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
- 来源:
- 关键词:Advanced Malignant NeoplasmAffectApoptosisAreaBasic ScienceBiological MarkersBiologyBreastC3H/HeN MouseCancer ModelCancer cell lineCell Culture TechniquesCellsComplementCredentialingDNADataDevelopmentDiagnosisDiseaseElementsEventExhibitsFemaleFrequenciesFutureGeneticGenotypeGoalsInfiltrationInflammatoryInheritedIntravenousIntrinsic factorLaboratoriesMalignant neoplasm of urinary bladderMeasuresMediatorMedicalMetastatic Neoplasm to the LungMitochondriaMitochondrial DNAModelingMouse StrainsMusNeoplasm MetastasisNitrosaminesNuclearOperative Surgical ProceduresOutcomePathogenicityPathway interactionsPatientsPhenotypePredispositionPrevention ResearchPreventive MedicinePrimary NeoplasmPrognostic FactorProliferatingProteinsPublic HealthResearchRibosomal RNARoleSamplingSignal TransductionSolid NeoplasmTarget PopulationsTherapeuticTissuesTransfer RNATransgenic MiceTumorigenicityVariantWorkadvanced diseaseangiogenesisbiomarker developmentcancer cellchemical carcinogenexperienceexperimental studyhuman diseaseimprovedlaser capture microdissectionlymph nodesmalignant breast neoplasmmelanomamouse modelneoplastic cellnovelprogramsresponsetranscriptome sequencingtumortumor initiationtumor progressiontumorigenesis
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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