Optogenetic Control of Tumor Initiation and Tumor Progression in vivo

体内肿瘤发生和进展的光遗传学控制

基本信息

批准号：
10640927
负责人：
ANDREI V KARGINOV
金额：
$ 38.09万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-08 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640927
关键词：
Animal Model Automobile Driving Biological Models Breast Cancer Cell Bypass Cancer Model Carcinogens Catalytic Domain Cells Complex DNA Data Development Disseminated Malignant Neoplasm Early treatment Endothelial Cells Endothelium Engineering Ensure Enterobacteria phage P1 Cre recombinase Environment Enzymes Epithelial Cells Funding Gene Expression Goals Grant Guanosine Triphosphate Phosphohydrolases Human Implant KDR gene KRAS oncogenesis Lesion Light Location Lung Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic Neoplasm to the Lung Methodology Methods Modeling Mus Mutation Nature Neoplasm Metastasis Oncogenes Oncogenic Organ Pathway interactions Patients Pattern Phase Process Protein Engineering Protein Kinase Proteins Publishing Regulation Reproducibility Research Personnel Role Signal Transduction Source System Systems Development anticancer research cancer cell cancer initiation cancer type circulating cancer cell design flexibility in vivo interest metastatic process mouse model neoplastic cell new technology novel novel strategies optogenetics overexpression protein expression research and development src-Family Kinases therapy development tool translational scientist tumor tumor initiation tumor progression tumorigenesis

项目摘要

Cancer research and therapy development rely heavily on animal models. One of the key features desired in a mouse model is ability to control tumor initiation and progression. However, existing methods cannot control where and when tumor will form and/or do not allow regulation of specific oncogenic signaling patterns driving tumor progression. Here we propose to develop an in vivo system that will provide tight control of oncogenic signaling with precise control of timing and location within a specific organ. To achieve spatial and temporal control of protein activity and gene expression we will use a novel optogenetic strategy that employs engineered light-regulated proteins. Our previous studies funded by an IMAT R21 grant allowed us to develop a Light- Regulated (LightR) domain that can function as allosteric switch to control protein activity. Using this method, we propose to develop in vivo strategy for regulation of oncogenic protein kinases and expression of oncogenes that drive initiation and progression of lung cancer as well as mediate development of metastatic lesions in the lung. The goal is to build a set of tools that will allow researcher to model oncogenic signaling in a specific organ and interrogate its role in tumor development and regulation of tumor environment. As model systems for development of new technology, we will develop a toolkit that enables regulation of oncogenic KRas expression and Src kinase activity at a selected location in mouse lungs with precise timing. These models will allow researchers to interrogate the role of KRas and Src in initiation of lung cancer, its progression, and spreading to other locations. We will also develop a system that will enable local regulation of oncogenic signaling promoting metastasis of circulating cancer cells in the lung. This method will enable regulation of specific stages of metastatic process. It will provide new tools for interrogation of oncogenic signaling in promoting metastatic ability of cancer cells and regulation of the pre-metastatic tumor niche in vivo. The design of the proposed systems will ensure their application for different cancer models.

癌症研究和治疗的开发很大程度上依赖于动物模型。所需的关键功能之一小鼠模型是控制肿瘤启动和进展的能力。但是，现有方法无法控制在何处以及何时形成肿瘤和/或不允许调节特定的致癌信号传导模式驱动肿瘤进展。在这里，我们建议开发一个体内系统，该系统将对致癌性进行严格的控制通过精确控制特定器官内的时间和位置的信号传导。实现空间和时间控制蛋白质活性和基因表达，我们将使用一种采用工程的新型光遗传策略光调节的蛋白质。我们以前由IMAT R21赠款资助的研究使我们能够开发一个光可以用作控制蛋白活性的变构切换的调节（LIGHTR）结构域。使用此方法，我们建议制定体内策略来调节致癌蛋白激酶和致癌基因的表达促进肺癌的启动和进展，并介导转移性病变的发展肺。目的是构建一组工具，使研究人员能够在特定器官中建模致癌信号并询问其在肿瘤发展和调节肿瘤环境中的作用。作为模型系统开发新技术，我们将开发一个工具包，以调节致癌性KRAS表达和SRC激酶活性在小鼠肺中精确时机的选定位置。这些模型将允许研究人员询问KRAS和SRC在肺癌开始，其进展以及扩散到肺癌中的作用其他位置。我们还将开发一个系统，该系统将促进致癌信号的局部调节肺中循环癌细胞的转移。此方法将对特定阶段进行调节转移过程。它将为促进转移性的致癌信号询问提供新的工具癌细胞的能力和体内近观念前肿瘤生态位的调节。提议的设计系统将确保其应用于不同的癌症模型。