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Exploring the Role of Mitochondrial Fission in Pancreatic Tumorigenesis

探索线粒体裂变在胰腺肿瘤发生中的作用

基本信息

批准号：
9004824
负责人：
David Francis Kashatus
金额：
$ 35.59万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9004824
关键词：
Animals Biochemical Biological Biological Models Biological Process Cancer Etiology Cancer cell line Cell Proliferation Cell physiology Cells Disease model Drug Targeting Ductal Equilibrium Event Exhibits Family Future GTP Binding Genes Genetic Engineering Genetically Engineered Mouse Goals Guanosine Triphosphate Phosphohydrolases Human Immune In Vitro Intervention Lead Link MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mitochondria Modeling Molecular Monomeric GTP-Binding Proteins Mutate Mutation Neoplasm Metastasis Oncogenic Organelles Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phosphorylation Phosphorylation Inhibition Physiological Play Pre-Clinical Model Process Property Publishing RAS genes Reagent Regulation Research Resistance Role Series System Testing Therapeutic Therapeutic Intervention Tumor Cell Line Work Xenograft Model Xenograft procedure cell transformation in vivo member mouse model mutant novel novel strategies pancreatic cancer cells pancreatic neoplasm pancreatic tumorigenesis public health relevance ras Proteins subcutaneous targeted treatment tumor tumor growth tumor initiation tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Over 90% of pancreatic cancers harbor a mutation in the Ras gene, yet identifying drugs that target the mutant Ras protein have proven difficult. Therefore, it is critical that we understand the biochemical and physiological changes elicited by mutant Ras so that we can identify drug targets more amenable to pharmacological intervention. To that end, Ras-driven pancreatic tumors are characterized by changes in mitochondrial function. The mitochondria are organelles present within the cell that are responsible for generating energy and providing the building blocks required for cellular proliferation. We have uncovered a novel link between the activity of Ras proteins and the cellular machinery that controls the fusion and fission of the mitochondria. Recent research indicates that the regulation mitochondrial fusion and fission greatly impacts mitochondrial function. We hypothesize that altering the balance of mitochondrial fusion and fission is required for mutant Ras to promote excess proliferation and that the mitochondrial fusion and fission machinery might represent an attractive drug target for pancreatic cancer. In aim 1, our goal is to elucidate the physiological consequences of Ras- induced mitochondrial fission in a series of patient-derived pancreatic cancer cell lines. In aims two and three, our goal is to use two complementary and physiologically relevant mouse models of pancreatic ductal adenocarcinoma to test the requirement of mitochondrial fission for pancreatic tumor growth and explore whether the mitochondrial fission machinery might be a viable drug target. Completion of these aims will give us a better understanding of the important role mitochondrial function plays in pancreatic cancer and allow us to identify novel targets for therapeutic intervention.