MECHANISMS UNDERLYING GENETIC DEFECTS IN COLON CANCER

描述（申请人的描述）：Eshleman博士获得了医学博士学位。和 博士在解剖学和结构生物学研究肌肉细胞生物学 来自宾夕法尼亚大学 他完成了住院医师、研究员和 在同一机构病理学系进行博士后培训 年加入凯斯西储大学病理学系 1993年，担任初级教师。 他目前的研究兴趣是癌症 生物学 他现在正在获得癌症和分子生物学方面的新专业知识， 和突变研究，这将使他能够开发一个独立的， 该领域的研究计划。 本提案的目标是确定分子机制和作用 在人类结肠癌发生中，四种新定义的，遗传上不同的， 结直肠癌（CRC）“突变体”表型。 他发现了这些变异体 通过证明在这些癌症中， 自发性HPRT突变率。 其中三种表型是 小说 这些观察结果扩展了他的赞助者以前的研究， 合作者证明了DNA微卫星的不稳定性 RER表型存在于遗传性和一些散发性 《儿童权利公约》。 他们证明，遗传性，而不是散发性，RER癌是由于 与DNA碱基错配修复相关的四个基因中的任何一个缺陷有关 （MMR）。 他定义的两种独特而新颖的表型是 哪些RER CRC是由不涉及已知MMR基因的缺陷产生的。 此外，他的研究第一次证明了一个 新的增变机制，诱导非RER CRC序列不稳定性。 这些增变基因表型的分析现在是这项建议的重点。 他 将通过确定这些新的表型的类型来表征这些新的表型。 在这些突变子中发生在hprt基因中的自发突变 背景，以确定不同类别的DNA修复系统， 在这些变构细胞中都不存在 他将决定 这些缺陷表型对环境因子诱导易感性 突变，这将提供深入了解环境的相互作用， 和遗传易感性。 他将进行基因 使用细胞杂交和转染的互补研究， 确定有多少潜在的基因缺陷赋予这些表型， 提供新的潜在缺陷的染色体位点的初始数据。 这些信息将提高他们对癌症发生的理解， 家族性和散发性突变型CRC。 博士Eshleman目前在凯斯西储大学的职位提供了 获得癌症和分子生物学专业知识的绝佳机会 和突变研究 他的赞助人马科维茨和塞德威克博士 在这些地区建立了调查人员。 病理学系和 医学和爱尔兰癌症中心将为他提供所有的 为这些研究提供必要的设施，以及丰富的知识分子 学术，临床和研究职业发展的环境。

DESCRIPTION (Applicant's Description): Dr. Eshleman received his M.D. and Ph.D. in Anatomy and Structural Biology for studies in muscle cell biology from the University of Pennsylvania. He completed residency, fellowship and postdoctoral training in the Department of Pathology at the same institution and joined the Department of Pathology at Case Western Reserve University in 1993 as a junior faculty member. His current research interest is cancer biology. He is now gaining new expertise in cancer and molecular biology, and in mutation research, which will enable him to develop an independent research program in this area. The goal of this proposal is to define the molecular mechanism and the role in human colon carcinogenesis of four newly defined, genetically distinct, colorectal cancer (CRC) "mutator" phenotypes. He has detected these mutator type CRC's by demonstrating in these cancers ten to 100 fold elevations of their rates of spontaneous hprt mutations. Three of these phenotypes are novel. These observations extend previous studies by his sponsors and collaborators which demonstrate that instability in DNA microsatellite sequences (RER phenotype) is present in both inherited and some sporadic CRC. They demonstrate that inherited, but not sporadic, RER cancers are due to defects in any of four genes involved in DNA base-base mismatch repair (MMR). Two of the distinct and novel phenotypes he defines are those in which RER CRCs are generated by defects not involving know MMR genes. Additionally, his studies demonstrate for the first time the existence of a novel mutator mechanism which induces sequence instability in non-RER CRCs. Analysis of these mutator phenotypes is now the focus of this proposal. He will characterize these novel phenotypes by determining the types of spontaneous mutations which occur in the hprt gene in these mutator backgrounds to identify the different classes of DNA repair systems which are absent in each of these mutator cells. He will determine the susceptibility of these deficient phenotypes to environmental agent induced mutations, which will provide insight into the interaction of environmental and genetic susceptibility in carcinogenesis. He will perform genetic complementation studies using both cell hybridization, and transfection, to determine how many underlying gene defects confer these phenotypes, and to provide initial data on the chromosomal locus of novel underlying defects. This information will enhance their understanding of carcinogenesis in familial and sporadic mutator CRC. Dr. Eshleman's current position at Case Western Reserve University provides an excellent opportunity to gain expertise in cancer and molecular biology and mutation research. His sponsors, Drs. Markowitz and Sedwick, are established investigators in these areas. The Departments of Pathology and Medicine and the Ireland Cancer Center will provide him with all of the necessary facilities for these studies, as well as a rich intellectual environment for academic, clinical, and research career development.