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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：
10413468
负责人：
ANDREI V KARGINOV
金额：
$ 40.36万
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/10413468
关键词：
Animal Model Automobile Driving Biological Models Breast Cancer Cell Bypass Cancer Model 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 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 recombinase 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.

癌症研究和治疗发展在很大程度上依赖于动物模型。的关键特性之一