Genes from the FAP Locus

描述(申请人提供)：结直肠癌是美国癌症死亡的主要原因，每年有135,000例新病例和55,000例死亡。这些病例中的绝大多数是由APC肿瘤抑制基因突变引起的。APC的突变导致良性肿瘤的形成，这些良性肿瘤通过癌基因和其他肿瘤抑制基因的后续突变而进展为恶性肿瘤。在这个过程中，肿瘤会颠覆正常的生理过程来支持它们的生长。这些过程中最主要的是通过刺激血管生成来提供血液供应。这项应用的目的是继续我们对APC途径和支持结直肠肿瘤生长的血管生成过程的成功分析。 目的#1.APC通路的表达分析。虽然关于APC途径已经了解了很多，但关于APC如何正常发挥作用以抑制肿瘤发生的确切分子细节仍然存在争议。这一目标旨在将体细胞敲除技术的力量与基因表达技术的进步相结合，以提供与APC和β-连环蛋白突变相关的基因表达变化的前所未有的视角。 目的#2.APC通路的功能分析。随着APC途径的继续定义和扩展，仔细定义每个成分的生物学功能将是至关重要的。虽然过度表达和RNA介导的抑制可以帮助这些分析，但基因敲除提供了在体细胞中评估这些参数的最严格的方法。本研究的目的是利用基因敲除技术仔细分析APC通路成员的生化和生物学功能，包括APC、β-连环蛋白、c-myc、CDK4、Cyclin D1和EB1。 目的#3.肿瘤血管生成的分子特征。我们以前已经发现了一系列基因，这些基因在人类结直肠癌血管内皮细胞中优先表达。本研究的目的是通过相互作用蛋白的鉴定、基因表达分析和小鼠基因敲除来确定选定的TEM的功能。 以上研究的结合应该为推动和支持结直肠肿瘤发展的过程提供重要的见解。

DESCRIPTION (provided by applicant): Colorectal cancer is a leading cause of cancer death in the United States with 135,000 new cases and 55,000 deaths each year. The great majority of these cases are initiated by mutations in the APC tumor suppressor gene. Mutations of APC result in the formation of benign tumors that progress to malignancy through subsequent mutations in oncogenes and other tumor suppressor genes. During this progression, tumors subvert normal physiological processes to support their growth. Chief among these processes is the provision of a blood supply through stimulation of angiogenesis. The aims of this application are directed at continuing our successful analyses of the APC pathway and the angiogenic processes that support colorectal tumor growth. Aim #1. Expression analysis of the APC pathway. While a great deal has been learned about the APC pathway, the precise molecular details of how APC normally functions to suppress tumorigenesis remain controversial. This aim is intended to couple the power of somatic cell knockout technology with advances in gene expression technology to provide an unprecedented view of the changes in gene expression associated with APC and Beta-catenin mutations. Aim#2. Functional analysis of the APC pathway. As the APC pathway continues to be defined and extended, it will be critical to carefully define the biological functions of each component. While over-expression and RNA mediated inhibition can aid in these analyses, genetic knockouts provide the most rigorous way to assess these parameters in somatic cells. This aim is intended to use genetic knockouts to carefully dissect the biochemical and biological functions of members of the APC pathway including APC, Beta-catenin, c-MYC, CDK4, Cyclin D1 and EB1. Aim #3. Molecular characterization of tumor angiogenesis. We have previously identified a series of genes that is preferentially expressed in the vessel endothelial cells from human colorectal cancers (TEMs). This aim is intended to define the function of selected TEMs through identification of interacting proteins, gene expression analysis and mouse knockouts. The combination of the above studies should provide important insights into the processes that drive and support colorectal tumor development.