Genes from the FAP Locus

这项提议是为了将功勋奖延长五年，以期在#年取得重大进展的基础上再接再厉。 目前的资助期。着眼于以往工作中最激动人心的方面，我们将集中精力 在以下三个方面。目的1.结直肠癌的表达分析。我们最有趣的一个 研究发现，正常人群和疾病人群的等位基因表达存在显著和意外的差异 各州。具体地说，我们证明了APC的一个等位基因的表达减少足以 导致疾病，等位基因表达变异在普通人群中很常见。然而， 遗传和躯体获得性等位基因表达变异对人类的影响程度 肿瘤的形成在很大程度上是未知的。为了解决这个问题，我们将对等位基因进行全面的评估 在人类结直肠癌中的表达。这项研究将有助于确定等位基因改变的程度和基础 在人类中的表达。癌症。那些由于沉默而显示等位基因表达改变的转录本 甲基化、无意义介导的衰退或启动子突变应该被证明是特别有趣的，并将 将成为进一步调查的对象。目的2.结直肠癌基因拷贝数分析。我们的一些人 最重要的发现是使用了癌症基因分析的新方法。在这个目标中， 我们将结合数字核型分析、SAGE和高通量突变分析来确定 结直肠癌中的扩增事件。我们将把我们的初步分析集中在扩增的基因上，以便 确定在治疗和诊断应用中通常具有更好特性的癌基因。 目的3.肿瘤血管发生的分子特征。我们对TEM的发现是 在肿瘤血管生成方面尤其具有启发性。TEM1 KO小鼠提供了对 间质组织在肿瘤生长和侵袭中的作用。同样，我们对TEM7和TEM7配体的鉴定 Temes揭示了意想不到的联系。我们将继续为实现这一目标而开展工作，具体做法是 TEMS和TEMS KO小鼠的特征。我们还将使用酵母双杂交和亲和纯化 筛选以识别TEMS配体。上述研究将为教师培训管理人员的作用提供更多的见解 在肿瘤血管生成和生长中的作用以及潜在地为其治疗应用提供线索 Temes.总体而言，拟议的研究应该为肿瘤血管生成提供重要的新见解(目标3)。 以及人类癌症基因改变的特定靶点(目标1和2)。 与公共卫生的相关性：癌症管理方面最令人兴奋的最新进展是 基于对这种致命疾病的分子和基因的了解。在这篇文章中提出的研究 应用的目的是确定肿瘤招募血管的分子基础，并 识别驱动癌症发展的基因改变。这两个途径都应该有助于推动新的 治疗方法和基因改变应该立即应用于早期诊断。

This proposal is for a five year extension of a Merit Award to build on the considerable progress made during the current funding period. Focusing on the most exciting aspect of our previous work, we will concentrate on the following three areas. AIM 1. Expression Analysis of Colorectal Cancer. One of our most interesting discoveries showed substantial and unexpected differences in allelic expression in normal and disease states. Specifically, we demonstrated that decreased expression from one allele of APC was sufficient to cause disease and that variation in allelic expression was common in the general population. However, the extent to which inherited and somatically acquired variations in allelic expression contribute to human neoplasia is largely unknown. To address this issue, we will perform a comprehensive evaluation of allelic expression in human colorectal cancer. This study will help define the extent and basis of altered allelic expression in human.cancer. Those transcripts displaying altered allelic expression due to silencing by methylation, nonsense mediated decay or promoter mutations should prove particularly interesting and will be the subject of further investigation. AIM 2. Copy Number Analysis of Colorectal Cancer. Some of our most important discoveries were made using new approaches for the genetic analyses of cancer. In this aim, we will combine Digital Karyotyping, SAGE and high throughput mutational analyses to define the targets of amplification events in colorectal cancers. We will focus our initial analysis on amplified genes in order to identify oncogenes which generally have better properties for therapeutic and diagnostic applications. AIM 3. Molecular Characterization of Tumor Anqiogenesis. Our discoveries of the TEMs have been particularly revealing with regards to tumor angiogenesis. The TEM1 KO mice provided new insights into the role of stromal tissue in tumor growth and invasion. Likewise, our identification of ligands for TEM7 and TEMS revealed unexpected associations. We will continue our work on this aim by generating and characterizing TEMS and TEMS KO mice. We will also use a yeast two hybrid and an affinity purification screen to identify TEMS ligands. The above studies will provide additional insights into the role of the TEMs in tumor angiogenesis and growth as well as potentially provide leads to the therapeutic applications of the TEMs. Overall, the proposed studies should provide important new insights into tumor angiogenesis (Aim 3) and the specific targets (Aims 1 & 2) of genetic alterations in human cancer. Relevance to Public Health: The most exciting recent advances in the management of cancer have been based on a molecular and genetic understanding of this deadly disease. The studies proposed in this application are directed at defining the molecular basis for the recruitment of blood vessels by tumors and at identifying the genetic alterations that drive cancer development. Both these avenues should help drive new therapeutic approaches and the genetic alterations should have immediate applications to early diagnosis.