权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
JOHN A TAYLOR
金额：
$ 21.74万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10575847
关键词：
Advanced Malignant Neoplasm Affect Apoptosis Area Basic Science Biological Markers Biology Breast C3H/HeN Mouse Cancer Model Cancer cell line Cell Culture Techniques Cells Complement Credentialing DNA Data Development Diagnosis Disease Elements Event Exhibits Female Frequencies Future Genetic Genotype Goals Infiltration Inflammatory Inherited Intravenous Intrinsic factor Laboratories Malignant neoplasm of urinary bladder Measures Mediator Medical Metastatic Neoplasm to the Lung Mitochondria Mitochondrial DNA Modeling Mouse Strains Mus Neoplasm Metastasis Nitrosamines Nuclear Operative Surgical Procedures Outcome Pathogenicity Pathway interactions Patients Phenotype Predisposition Prevention Research Preventive Medicine Primary Neoplasm Prognostic Factor Proliferating Proteins Public Health Research Ribosomal RNA Role Sampling Signal Transduction Solid Neoplasm Target Populations Therapeutic Tissues Transfer RNA Transgenic Mice Tumorigenicity Variant Work advanced disease angiogenesis biomarker development cancer cell chemical carcinogen experience experimental study human disease improved laser capture microdissection lymph nodes malignant breast neoplasm melanoma mouse model neoplastic cell novel programs response transcriptome sequencing tumor tumor initiation tumor progression tumorigenesis

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