Modeling Airway Lung Cancer and the Role of Inflammation

描述(由申请人提供)： 肺是一个复杂的器官，其主要功能是允许体液和外部环境之间的气体交换。毒素的持续暴露使肺上皮细胞高度易感致癌转化，导致肺癌的发生。肺癌是美国男女癌症相关死亡的主要原因，这一事实证明了这一点。建立模拟肺癌的突变小鼠将有助于了解这种疾病发展的分子机制，并有助于开发早期发现和治疗这种疾病的手段。在小鼠身上建立肺癌模型并不是一件简单的事情。肺癌不是一种独特的疾病，但可以分为四种主要的、组织学上可识别的亚型[Ei-Torky，1990#3]。这些亚型包括腺癌、鳞癌、小细胞癌和大细胞癌。目前，鳞状细胞癌和腺癌是美国最常见的肺癌类型，腺癌是女性最常见的肺癌形式。事实上，腺癌已经增加到支气管癌的45%，鳞癌和大细胞癌的比例下降，而小细胞癌保持在20%。这个MMHCC应用程序的目标是通过创建基因修饰来破坏与人类肺癌相关的特定基因或途径，从而开发出肺腺癌的小鼠模型。这些修改将针对小鼠呼吸道的一种特定细胞类型，即Clara细胞。一旦确定了这些模型中癌症进展的特征，就将确定炎症在这些模型中癌症进展中所起的作用。对这些模型的分析包括对癌症进展过程中分子变化的最新成像和DNA和蛋白质组学分析。

DESCRIPTION (provided by applicant): The lung is a complex organ with the primary function of allowing the exchange of gasses between the body fluids and the external environment. The constant exposure to toxins makes the pulmonary epithelial cells highly susceptible to oncogenic transformation, leading to the development of lung cancer. This is borne by the fact that lung cancer is the leading cause of cancer related death in both sexes in the United States. The establishment of mutant mice that mimic the lung cancer will aid in the understanding of the molecular mechanisms regulating the development of this disease as well as aid in the development of means of early detection and the treatment of this disease. Modeling lung cancer in mice is not a simple task. Lung cancer is not one distinct disease but can be divided into four major, histologically identifiable subtypes [eI-Torky, 1990 #3]. These subtypes are adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and large cell carcinoma. Currently, squamous cell carcinoma and adenocarcinoma are the most common type of lung cancer in the United States with adenocarcinoma being the most common form of lung cancer in women. In fact adenocarcinoma has increased to 45% of bronchogenic carcinomas with declines in squamous and large cell carcinomas, while small cell has remained at 20%. The goal of this MMHCC application is to develop mouse models for adenocarcinoma of the lung by creating genetic modifications that disrupt specific genes or pathways that have been associated with human lung cancer. These modifications will be targeted to one specific cell type of the mouse airways, the Clara cell. Once these progressions of cancer in these models have been characterized, the role inflammation plays in the progression of cancer in these models will be determined. The analysis of these models includes state of the art imaging and DNA and proteomic analysis of the molecular changes during cancer progression.