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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）：放射治疗用于治疗约50%的癌症患者。然而，在提高放射治疗的疗效方面的一个根本差距是，放射治疗控制肿瘤的机制仍然知之甚少。例如，肿瘤内皮细胞是否是介导肿瘤治愈的放射治疗的关键靶点是有争议的。本研究的总体目标是确定放射治疗的细胞靶点：肿瘤细胞（此处称为肿瘤实质细胞）与内皮细胞该应用的中心假设是放射疗法通过杀死肿瘤实质细胞而不是肿瘤内皮细胞来治愈癌症。为了研究肿瘤内皮细胞和肿瘤实质细胞作为放射治疗靶点的相对贡献，我们产生了新型基因工程小鼠。以前，我们使用Cre重组酶开发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。我们现在已经产生了新的基因工程小鼠品系，其中原发性癌症可以用Flp重组酶产生。在该系统中，Cre重组酶仍然可以用于特异性修饰肿瘤内皮细胞中的基因。利用Flp和Cre重组酶（即双重组酶技术）来研究肿瘤内皮细胞在放射治疗中的作用是高度创新的，因为原发性癌症可以用一种重组酶启动，而另一种重组酶可以用于特异性地修饰内皮细胞的放射敏感性。这项研究意义重大，因为它将澄清肿瘤内皮细胞是否是放射治疗的关键靶点。最终，这些知识有可能为提高放射治疗疗效的新方法奠定基础。