Novel O-glycosylation Gene Mutations in Colon Cancer

简介（申请人提供）：我是凯斯西储大学综合癌症中心医学系的一名研究讲师。我的主要导师是桑福德·马科维茨博士。我的短期目标是在拟议的癌症糖基化研究领域获得必要的理论和技术技能，我的长期目标是进行有关癌症易感性和进展的分子方面的转化研究。本提案的长期目标是识别和确定o -糖基化途径缺陷在结肠肿瘤发病机制中的作用。蛋白糖基化是参与多种细胞过程的基本机制。异常糖基化是几种人类癌症的标志，已被认为对细胞稳态过程有深远的影响。迄今为止，异常糖基化的潜在分子基础及其在致瘤过程中的作用在很大程度上仍然未知。最近，我在结肠癌患者中发现了编码n -乙酰半乳糖氨基转移酶12 （GALNT12）基因的失活种系和体细胞突变，该基因催化粘蛋白型o糖基化的起始步骤。这些发现为结肠癌o糖基化途径存在遗传缺陷提供了第一个证据，并表明在结肠癌和其他癌症中常见的异常糖基化在某些情况下可能是由糖基转移酶基因突变引起的原发性异常，并直接导致癌症表型。本研究的主要目标是：a)检测结肠癌中编码o -聚糖生物合成酶的额外o -糖基化途径基因突变的存在；b)确定GALNT12和其他o -糖基化基因的双等位基因失活是否对结肠肿瘤的发展至关重要；c)建立小鼠模型，以确定GALNT12的缺失是否会增强结肠癌的易感性。d)利用蛋白质组学技术鉴定在结肠肿瘤发展中起作用的GALNT12内源性蛋白靶点。作为我职业发展计划的一部分，我将在糖生物学、蛋白质组学和遗传流行病学领域接受必要的教学培训。与我的共同导师Thomas Gerken博士和Robert Elston博士一起，Markowitz博士和他的团队将为我提供一个优秀的研究和教育环境，这将有助于推进我成为癌症糖基化研究独立研究者的目标。

DESCRIPTION (provided by applicant): I am a Research Instructor in the Department of Medicine at the Case Western Reserve University Comprehensive Cancer Center. My primary mentor is Dr. Sanford Markowitz. My short-term objectives are to gain the necessary theoretical and technical skills in the proposed area of cancer glycosylation research, and my long-term goal is to conduct translational research pertaining to the molecular aspects of cancer predisposition and progression. The long range objectives of this proposal are to identify and determine the role of O-glycosylation pathway defects in the pathogenesis of colon neoplasia. Protein glycosylation is a fundamental mechanism involved in multiple cellular processes. Aberrant glycosylation is a hallmark of several human cancers that has been suggested to have a profound effect on the cellular homeostatic processes. To date, the underlying molecular basis of aberrant glycosylation and its role in the tumorigenic process however remains largely unknown. Recently, I discovered inactivating germline and somatic mutations in the gene encoding for N-acetylgalactosaminyl transferase12 (GALNT12), which catalyzes the initiating step in mucin type O-glycosylation, in individuals with colon cancer. These findings provide the first evidence for the presence of genetic defects in the O-glycosylation pathway in colon cancers, and suggest that aberrant glycosylation commonly seen in colon and other cancers may in some instances represent a primary abnormality resulting from mutations in glycosyltransferase genes, and directly contributing to the cancer phenotype. The major goals of this proposal are, a) to examine colon cancers for the presence of mutations in additional O-glycosylation pathway genes that encode for enzymes involved in O-glycan biosynthesis, b) to determine whether bi-allelic inactivation of GALNT12 and other O-glycosylation genes is essential for colon tumor development, c) to develop mouse models to determine if loss of GALNT12 enhances the susceptibility to colon carcinogenesis, and d) to employ proteomic techniques to identify endogenous protein targets of GALNT12 that play a role in colon tumor development. As part of my career development plan, I will undergo the necessary didactic training in the field(s) of glycobiology, proteomics and genetic epidemiology. Along with my co-mentors Dr. Thomas Gerken and Dr. Robert Elston, Dr. Markowitz and his group will provide me with an outstanding research and educational environment that will help in advancing my goal of becoming an independent investigator in cancer glycosylation research.