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Identifying and Targeting Mechanisms for Membrane Signaling in Human Cancer

人类癌症膜信号传导的识别和靶向机制

基本信息

批准号：
10521275
负责人：
PETER Kent JACKSON
金额：
$ 54.32万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-10 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521275
关键词：
3-Dimensional AGFG1 gene Adenocarcinoma Affinity Chromatography Apical Apoptosis Automobile Driving Binding Biochemical Biochemistry Biological Models Biophysics CRISPR/Cas technology Cancer Etiology Cell Line Cell Proliferation Cell membrane Cells Cellular biology Cessation of life Collaborations Complex Coupled Data Dependence Endosomes Epithelial Cells Exons Family Family member Frequencies Funding Genes Genetic Genetically Engineered Mouse Genomics Genotype Goals Grant Growth Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Human In Vitro KRAS oncogenesis KRAS2 gene Knock-out Laboratories Libraries Link Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Membrane Modeling Molecular Molecular Chaperones Monomeric GTP-Binding Proteins Mus Mutate Mutation National Cancer Institute Non-Small-Cell Lung Carcinoma Oncogenic Pathway interactions Phenotype Physicians Pre-Clinical Model Principal Investigator Proliferating Protein Analysis Protein Family Protein Isoforms Proteins Proteomics RAS genes Regulation Role Scientist Series Shotguns Signal Pathway Signal Transduction Specificity Testing Therapeutic Therapeutic Effect Tissues Xenograft procedure bronchial epithelium candidate validation cell growth combinatorial design drug discovery experience experimental study functional genomics gene interaction genetic analysis genetic approach human model in vivo inhibitor innovation knockout gene mouse model mutant novel novel therapeutic intervention overexpression patient derived xenograft model prenylation protein protein interaction rab GTP-Binding Proteins recruit rho therapeutically effective

项目摘要

PROJECT SUMMARY Lung cancer is the leading cause of cancer deaths worldwide. The most prevalent type of lung cancer is Non- Small Cell Lung Cancer (NSCLC). Within NSCLC, the most common subtype is adenocarcinoma (LUAD). The goal of this application is to implement a collaborative effort involving two PIs with complimentary expertise in preclinical models, proteomics and functional genomics to understand the role of RhoA and RAP1GDS1 in driving oncogenic KRAS in LUAD Our extensive preliminary data indicates that blockade of combined loss of RhoA and RAP1GDS1 leads to decreased proliferation and increased apoptosis in a KRAS-dependent manner. The Sweet-Cordero and Jackson laboratories have collaborated intensively over the past several years first to identify this synthetic vulnerability and second to understand the mechanistic basis underlying it. In Aim 1, we will use functional and cell biology approaches to define the role of RAP1GDS1 in cell proliferation and growth in 3D. We will also expand our studies to evaluate the role of other Rho proteins as interactors with RAP1GDS1. In Aim 2, we will use proteomic approaches to further elucidate the consequences of RAP1GDS1 loss and specifically the differences between the long and short isoforms of this protein in the regulation of cell signaling. Finally, in Aim 3, we propose a series of experiments involving both PDX models of LUAD and GEM models of LUAD to further elucidate the genotype specificity of the interaction between RAP1GDS1 and RhoA. We will also explore the potential therapeutic implications of this combined vulnerability using Rock inhibitors and inhibition of RAP1GDS1 interaction with key downstream proteins.

项目总结