Defining the Cellular Target of Radiation Therapy

定义放射治疗的细胞靶点

基本信息

批准号：
8638098
负责人：
David Guy Kirsch
金额：
$ 20.49万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638098
关键词：
Adenoviruses Animals Apoptosis Cancer Biology Cancer Control Cancer Patient Cell Death Cells DNA Damage Dextrans Endothelial Cells Extravasation Foundations Future Gene-Modified Genes Genetically Engineered Mouse Goals In Vitro Injury Knowledge Lead Lung Malignant Neoplasms Malignant neoplasm of lung Mediating Mission Molecular Weight Mus Mutate Myocardial National Cancer Institute Non-Small-Cell Lung Carcinoma Normal tissue morphology Pathway interactions Patients Play Population Primary Neoplasm Public Health Radiation Radiation Tolerance Radiation therapy Radiobiology Relative (related person)Research Research Support Role Stromal Cells System Targeted Radiotherapy Technology Vascular Permeabilities Work cadherin 5 cancer therapy cellular targeting clinical care design dextran gastrointestinal improved in vivo innovation insight irradiation killings lung sarcoma mouse model neoplastic cell novel novel strategies public health relevance recombinase response sarcoma soft tissue tool tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Radiation therapy is utilized to treat approximately 50% of all patients with cancer. However, a fundamental gap in improving the efficacy of radiation therapy is that the mechanisms by which radiotherapy controls tumors remain poorly understood. For example, it is controversial whether tumor endothelial cells are a critical target of radiation therapy, which mediate tumor cure. The overall goal of this research is to define the cellular target of radiation therapy: tumor cells (referred to here as tumor parenchymal cells) vs. endothelial cells. The central hypothesis of this application is that radiation therapy cures cance by killing tumor parenchymal cells rather than tumor endothelial cells. To study the relative contribution of tumor endothelial cells and tumor parenchymal cells as targets of radiation therapy, we have generated novel genetically engineered mice. Previously, we used Cre recombinase to develop genetically engineered mouse models of lung cancer and soft tissue sarcoma to study radiation biology. We have now generated novel strains of genetically engineered mice in which primary cancers can be generated with Flp recombinase. In this system, Cre recombinase can still be utilized to modify genes specifically in tumor endothelial cells. Utilizing Flp and Cre recombinases (ie dual recombinase technology) to study the role of tumor endothelial cells in radiation therapy is highly innovative because primary cancers can be initiated with one recombinase, while the other recombinase can be utilized to specifically modify the radiosensitivity of the endothelial cells. The proposed research is significant, because it will clarify whether tumor endothelial cells are a critical target for radiation therapy Ultimately, such knowledge has the potential to lay the foundation for novel approaches to improve the efficacy of radiation therapy.

描述（由申请人提供）：用于治疗大约50％的所有癌症患者。然而，提高放射治疗功效的基本差距是放射疗法控制肿瘤的机制仍然鲜为人知。例如，肿瘤内皮细胞是否是介导肿瘤治愈的辐射疗法的关键靶标是有争议的。这项研究的总体目的是定义放射治疗的细胞靶标：肿瘤细胞（此处称为肿瘤实质细胞）vs。内皮细胞。该应用的中心假设是辐射疗法通过杀死肿瘤实质细胞而不是肿瘤内皮细胞来固化CANCE。为了研究肿瘤内皮细胞和肿瘤实质细胞作为放射疗法的靶标的相对贡献，我们产生了新型的基因工程小鼠。以前，我们使用CRE重组酶开发了肺癌和软组织肉瘤的基因工程小鼠模型来研究辐射生物学。现在，我们已经产生了新型的基因工程小鼠菌株，其中可以用FLP重组酶产生主要的癌症。在该系统中，CRE重组酶仍然可以用于在肿瘤内皮细胞中特异性修饰基因。利用FLP和CRE重组酶（即双重重组酶技术）来研究肿瘤内皮细胞在放射治疗中的作用非常创新，因为可以用一种重组酶启动原发性癌症，而另一种重组酶则可以利用以特异性修饰内皮细胞的辐射率。拟议的研究很重要，因为它将阐明肿瘤内皮细胞是否最终是放射治疗的关键目标，因此这种知识有可能为提高放射治疗的疗效的新方法奠定基础。