Mouse Models of Skin Cancer

描述(由申请人提供)： 紫外线照射是人类皮肤鳞状细胞癌和基底细胞癌的主要病因，也是黑色素瘤的危险因素。紫外线辐射诱发肿瘤的分子途径包括遗传和表观遗传事件。虽然启动事件通常是不可逆的，但至少与促进和进展相关的一些过程可以被有效地抑制或逆转，从而降低肿瘤的发生率和严重程度。这项研究的目的是确定三个过程和途径，即增殖、存活和/或炎症/血管生成在鳞状细胞癌发展中的相对重要性。我们建议通过对紫外线敏感的SKH-1无毛小鼠的遗传操作，确定控制每个过程的关键信号分子和通路，并确定哪一个更重要。现有证据表明，NFkB通路、Akt通路、STAT3通路和Rb-E2F1通路可调控细胞周期过程和细胞存活，而炎症则受NFkB通路调控，因此这些通路可能控制肿瘤发生的关键过程。这项研究的目标将通过回答以下问题来实现：1)细胞存活对皮肤癌有多重要？2)炎症和血管生成对皮肤癌有多重要？3)细胞周期基因的表达变化对皮肤癌有多重要？这些问题将通过使用现有的鼠标模型来解决，或者在需要时通过开发新的模型来解决。这些模型也将提供给其他研究人员用于他们对途径和紫外线致癌的研究。这一综合性项目的具体目标是：(1)将现有的与增殖、凋亡和炎症/血管生成相关的基因修饰转移到SKH-1无毛背景中，SKH-1是紫外线致癌研究中最有用的菌株。这包括STAT3、Akt、VEGF和Cre的转基因，以及Cyclin D1、CDK4、E2F1、Rb、STAT3、Bclxl、VEGF和IL-1R1的缺失(基因敲除)。这将使用速度同源方法来完成。(2)使用诱导式系统创建所需的新SKH-1无毛模型。靶向诱导性转基因(Bcl2、Bclxl、FasL、NFkB(P50)、IL-1a和诱导性条件性转基因(Akt、FasL、Bcl2和NFkB(P50))将使用基因交换方法进行。(3)在需要的情况下，将开发具有多种基因改变的模型。

DESCRIPTION (provided by applicant): Exposure to ultraviolet (UV) light is the major etiologic event for cutaneous squamous and basal cell carcinomas in humans and is also a risk factor for melanoma. The molecular pathways responsible for UV irradiation-induced tumors involve genetic and epigenetic events. While initiation events are generally irreversible, at least some of the processes associated with promotion and progression can be effectively inhibited or reversed, leading to a reduction in tumor incidence and severity. The goal of the proposed study is to determine the relative importance of each of three processes and pathways, i.e., proliferation, survival and/or inflammation/angiogenesis on the development of squamous cell carcinoma. We propose to identify the key signaling molecules and pathways that control each of these processes and determine which is more important, through use of genetic manipulation of the UV-sensitive SKH-1 hairless mouse. Available evidence indicates that cell cycle processes and cell survival can be regulated by the NFkB pathway, the Akt pathway, the stat3 pathway, and the Rb-E2F1 pathway while inflammation is regulated by the NFkB pathway, thus these pathways may control critical processes in cancer development. The goal of this study will be approached through answering the following questions: 1) How important is cell survival to skin cancer? 2) How important is inflammation and angiogenesis to skin cancer? 3) How important are alterations in the expression of cell cycle genes to skin cancer? These questions will be addressed through the use of existing mouse models, or where needed, through the development of new models. These models will also be made available to other investigators for their studies of pathways and UV carcinogenesis. The specific aims of this comprehensive Project are: (1) Transfer existing genetic modifications relating to proliferation, apoptosis and inflammation/angiogenesis onto the SKH-1 hairless background, the most useful strain for UV carcinogenesis studies. This includes transgenes for stat3, Akt, VEGF and Cre, and deficiencies (knockout) for cyclin D1, cdk4, E2F1, Rb, stat3, Bcl-xL, VEGF and IL-1R1. This will be done using the speed congenic approach. (2) Create needed new SKH-1 hairless models using inducible systems. Targeted inducible transgenics (Bcl2, Bcl-xL, FasL, NFkB(p50), IL-la and inducible conditional transgenics (Akt, FasL, Bcl2 and NFkB(p50), will made using gene switch approaches. (3) Where indicated, models with multiple genetic alterations will be developed.