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Investigation of the mitochondrial function in GNAS mutant neoplasms

GNAS 突变肿瘤中线粒体功能的研究

基本信息

批准号：
9721914
负责人：
Krushna Chandra Patra
金额：
$ 19.52万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9721914
关键词：
Acetyl Coenzyme A Acetyl Coenzyme A Address Address Amino Acid Metabolism Pathway Amino Acid Metabolism Pathway Biological Assay Biological Assay Biological Models Biological Models Branched-Chain Amino Acids Branched-Chain Amino Acids Cells Cells Citric Acid Cycle Citric Acid Cycle Coupled Coupled Cyclic AMP Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Dependent Protein Kinases Data Data Dependence Dependence Development Development Equilibrium Equilibrium Exhibits Exhibits FADH2 FADH2 Fatty Acids Fatty Acids Foundations Foundations GTP-Binding Proteins GTP-Binding Proteins Genetic Genetic Genetically Engineered Mouse Genetically Engineered Mouse Gnas protein Gnas protein Goals Goals Growth Growth Hot Spot Hot Spot Human Human Implant Implant Investigation Investigation Lead Lead Lipids Lipids Maintenance Maintenance Malignant Neoplasms Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Malignant neoplasm of pancreas Maps Maps Mediating Mediating Metabolic Metabolic Metabolic Pathway Metabolic Pathway Metabolism Metabolism Microscopy Microscopy Mitochondria Mitochondria Mitochondrial Proteins Mitochondrial Proteins Modeling Modeling Mus Mus Mutation Mutation NADH NADH Neoplasms Neoplasms Normal Cell Normal Cell Normal tissue morphology Normal tissue morphology Nutrient Nutrient Oncogenes Oncogenes Oncogenic Oncogenic Organoids Organoids Pancreatic Ductal Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pathway interactions Pathway interactions Patients Patients Pharmacology Pharmacology Physiological Processes Physiological Processes Process Process Production Production Protein Subunits Protein Subunits Proteins Proteins Proteome Proteome Proteomics Proteomics Publishing Publishing Reaction Reaction Recurrence Recurrence Regulation Regulation Role Role Series Series Signal Pathway Signal Pathway Signal Transduction Signal Transduction Solid Solid Structure Structure Testing Testing Therapeutic Therapeutic Up-Regulation Up-Regulation aerobic glycolysis aerobic glycolysis amino acid metabolism amino acid metabolism base base cancer cell cancer cell cancer subtypes cancer subtypes cancer type cancer type experimental study experimental study fatty acid oxidation fatty acid oxidation gain of function mutation gain of function mutation innovation innovation metabolomics metabolomics mitochondrial metabolism mitochondrial metabolism mutant mutant neoplastic cell neoplastic cell new therapeutic target new therapeutic target pancreatic tumorigenesis pancreatic tumorigenesis patient population patient population preclinical study preclinical study programs programs protein expression protein expression salt-inducible kinase salt-inducible kinase subcutaneous subcutaneous targeted treatment targeted treatment tumor tumor tumor growth tumor growth tumor initiation tumor initiation tumorigenesis tumorigenesis

项目摘要

Emerging evidences pointing out the requirement of mitochondrial function in the oncogenesis processes, but how the mitochondrial state is changed in different set of oncogenic mutations is largely obscure. Changes in mitochondrial metabolism and function are results of mitochondrial dynamics (fission/fusion) and remodeled mitochondrial proteome. cAMP/PKA pathway has conserved roles in the regulation of mitochondrial function and dynamics in various physiological processes. The goal of this proposal is to comprehensively analyze the mitochondrial function and state in a subset of pancreatic cancer those harbor gain-of-function mutations of GNAS (~60%). In a recent study I discovered mutant GNAS activates cAMP/PKA pathway that leads to inactivation salt-inducible-kinases (SIKs) and rewiring metabolic processes, a major mechanism required for tumor growth of these tumors. The global multiplex proteomics data revealed selective remodeling of cellular proteome by mutant GNAS activation. Specifically there is enrichment proteins of fatty acid oxidation (FAO) and branched chain amino acid (BCAA) pathways, which are compartmentalized in the mitochondria. Based on these preliminary data and the pivotal role of cAMP/PKA in controlling mitochondrial dynamics and metabolism, I hypothesize that mitochondria has profound roles in the oncogenesis process by mutant GNAS. Building on the solid foundation, this K22 proposal aims to map the GNAS-PKA-SIK mediated changes in mitochondrial dynamics and proteomic landscape. It will test the hypothesis that the changes in dynamics and proteome remodeling lead to altered FAO and BCAA pathway function, which are required for growth of GNAS mutant tumors. Using state-of-art organellar purification, proteomics, metabolic tracing and coupled with functional assays in pancreatic cancer organoids; I seek to identify the key function of mitochondria in GNAS mutant cancer. Results from these studies will give unparalleled understanding of oncogenic cAMP signaling in cancer and may lead to development of new-targeted therapies that can be used in genetically-defined patient populations.

越来越多的证据表明，在肿瘤发生过程中需要线粒体的功能，但线粒体状态在不同的致癌突变中是如何改变的，目前还很不清楚。中的更改线粒体的代谢和功能是线粒体动力学(分裂/融合)的结果，并被重塑线粒体蛋白质组。CAMP/PKA通路在线粒体功能调节中的保守作用以及各种生理过程中的动态变化。这项建议的目标是全面分析胰腺癌中携带功能获得突变的一组患者的线粒体功能和状态 GNAS(~60%)。在最近的一项研究中，我发现突变的GNAS激活cAMP/PKA途径，从而导致失活盐诱导激酶(SIKs)和重新连接代谢过程，这是这些肿瘤的肿瘤生长。全球多重蛋白质组学数据显示细胞选择性重塑通过突变的GNAS激活的蛋白质组。具体地说，存在脂肪酸氧化浓缩蛋白(粮农组织) 和支链氨基酸(BCAA)途径，它们在线粒体中被分割。基座关于这些初步数据和cAMP/PKA在控制线粒体动力学和关于新陈代谢，我假设线粒体在突变的GNAS的肿瘤形成过程中发挥着深远的作用。在坚实的基础上，这项K22提案旨在绘制GNAS-PKA-SIK在线粒体动力学和蛋白质组学图景。它将检验这样一种假设，即动态变化和蛋白质组重构导致FAO和BCAA途径功能改变，这是GNAS生长所必需的突变的肿瘤。使用最先进的细胞器纯化，蛋白质组学，代谢示踪和与胰腺癌类器官的功能分析；我试图确定线粒体在GNAS中的关键功能突变癌症。这些研究的结果将给我们对致癌cAMP信号的无与伦比的理解癌症，并可能导致新的靶向治疗的开发，可用于基因定义的患者人口。