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：
10317119
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/10317119
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 Complex Coupled Data Dependence 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 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 cell growth combinatorial design drug discovery experience experimental study functional genomics 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.

项目摘要肺癌是全球癌症死亡的主要原因。最普遍的肺癌类型是非 - 小细胞肺癌（NSCLC）。在NSCLC中，最常见的亚型是腺癌（LUAD）。这该应用程序的目标是实施一项协作努力，涉及两个PI，具有免费专业知识临床前模型，蛋白质组学和功能基因组学了解RhoA和Rap1GDS1在在LUAD中驱动致癌性Kras我们的广泛初步数据表明 RhoA和Rap1GDS1导致KRAS依赖性中的增殖和凋亡增加方式。在过去的几次几年首先确定这种综合脆弱性，其次是了解其基础的机械基础。在AIM 1中，我们将使用功能和细胞生物学方法来定义RAP1GDS1在细胞中的作用 3D的增殖和增长。我们还将扩大研究，以评估其他Rho蛋白的作用与RAP1GDS1的交互者。在AIM 2中，我们将使用蛋白质组学方法进一步阐明 RAP1GDS1损失的后果，特别是在此的长同工型之间的差异细胞信号传导调节中的蛋白质。最后，在AIM 3中，我们提出了一系列涉及的实验 LUAD的PDX模型和LUAD的宝石模型，以进一步阐明相互作用的基因型特异性在Rap1gds1和Rhoa之间。我们还将探讨这种合并的潜在治疗含义使用岩石抑制剂和抑制RAP1GDS1与关键下游蛋白相互作用的脆弱性。