MECHANISMS UNDERLYING GENETIC DEFECTS IN COLON CANCER

描述(申请人描述)：Eshleman博士获得医学博士学位并 肌肉细胞生物学研究的解剖学和结构生物学博士 来自宾夕法尼亚大学。他完成了住院医师资格，研究金和 同一机构病理学系的博士后培训 年加入凯斯西储大学病理系 1993年担任初级教员。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， 在突变研究中，这将使他能够开发出独立的 这一领域的研究计划。 这项提议的目标是定义分子机制和作用 在人类结肠癌的发生中，有四个新定义的、遗传上截然不同的 结直肠癌(CRC)“突变”表型。他发现了这些变种人 通过在这些癌症中展示10到100倍的隆起来分型结直肠癌 他们的HPRT自发突变率。这些表型中有三种是 小说。这些观察结果延续了他的赞助人之前的研究， 证明DNA微卫星不稳定的合作者 序列(RER表型)既存在于遗传性的，也存在于一些散发的 CRC。他们证明了遗传性的但不是散发的RER癌症是由于 与DNA碱基错配修复有关的四个基因中的任何一个的缺陷 (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，他的研究首次证明了一种 在非RER-CRCs中诱导序列不稳定性的新的突变体机制。 对这些突变子表型的分析现在是这项提案的重点。他 将通过确定这些新的表型的类型来表征 在这些突变子中HPRT基因发生的自发突变 背景识别不同类别的DNA修复系统 在这些突变子细胞中都不存在。他将决定 这些缺陷表型对环境诱导剂的敏感性 突变，这将提供对环境相互作用的洞察 以及致癌过程中的遗传易感性。他将表演遗传基因 同时使用细胞杂交和转基因的互补研究，以 确定有多少潜在的基因缺陷赋予这些表型，并 提供关于新的潜在缺陷的染色体位置的初始数据。 这些信息将增强他们对癌症发生的理解 家族性和散发性突变型CRC。 埃什尔曼博士目前在凯斯西储大学的职位提供 获得癌症和分子生物学专业知识的绝佳机会 和突变研究。他的赞助商Markowitz博士和Sedwick博士 这些领域的资深调查人员。病理科和医学系 医学和爱尔兰癌症中心将为他提供所有 为这些研究提供必要的设施，以及丰富的知识分子 学术、临床和研究事业发展的环境。

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.