Neoglycosylation Epitopes in Metaplasia and Cancer

化生和癌症中的新糖基化表位

• 批准号: 10429395
• 负责人: Jeffrey Wade Brown
• 金额: $ 16.66万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10429395
• 关键词: Advisory Committees; Barrett Esophagus; Binding; Biological Assay; Biological Markers; Cancer Etiology; Career Choice; Cell Differentiation process; Cell Line; Cell Maturation; Cell physiology; Cells; Characteristics; Chief Cell; Cytoplasmic Granules; Development Plans; Diagnosis; Doctor of Medicine; Doctor of Philosophy; E-Cadherin; Ensure; Epitopes; Fellowship; Fractionation; Funding; Galactose Binding Lectin; Galectin 3; Gastroenterology; Gene Chips; Gene Deletion; Gene Expression Profile; Genes; Genetic Models; Genetic Transcription; Glean; Glycobiology; Goals; Greek; High grade dysplasia; Homeostasis; Immunoelectron Microscopy; Immunofluorescence Immunologic; In Vitro; Intestinal Metaplasia; K-Series Research Career Programs; Knock-out; Knockout Mice; Knowledge; LS174T colon cancer cell line; Label; Laboratories; Lysosomes; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Medicine; Membrane; Mentors; Mentorship; Metaplasia; Metaplastic Cell; Molecular; Monitor; Mucins; Mus; Oncogenic; Organoids; Pancreatic cystic neoplasia; Phenotype; Polysaccharides; Positioning Attribute; Primitive foregut structure; Process; Production; Program Development; Proteins; Proteome; Repression; Research; Research Personnel; Risk; Role; Sialic Acids; Signal Pathway; Signal Transduction; Stomach; Sulfate; System; Technical Expertise; Techniques; Tissues; Transmission Electron Microscopy; Universities; Washington; Work; apical membrane; career development; cell dedifferentiation; clinically significant; experimental study; gastric intestinal metaplasia; glycosylation; high risk; instructor; loss of function; malignant stomach neoplasm; medical schools; metaplastic cell transformation; mortality; mouse model; novel; prevent; programs; protein transport; sialylation; skills; small molecule inhibitor; success; sulfomucin; tool; trafficking; tumorigenesis

PROJECT SUMMARY / ABSTRACT This application proposes a five-year research career development program focused on determining how glycosylation epitopes expressed during metaplasia and cancer contribute to these clinically significant cellular transformations. The applicant, Jeffrey W. Brown, M.D., Ph.D., is an Instructor of Medicine in the Division of Gastroenterology at Washington University School of Medicine. Since completing gastroenterology fellowship, Dr. Brown had worked in the laboratory of Jason Mills, where he has discovered a novel cellular process that he calls cathartocytosis [Greek: cellular cleansing] which is used by cells to efficiently dedifferentiate in the processes of metaplasia and cancer. He has subsequently determined that cathartocytosis is annotated by the glycan 3’-Sulfo-LeA/C and mice null for galectins that preferentially bind this epitope either fail to perform cathartocytosis or fail to package sulfomucins into mature granules. As glycobiology is a new field for Dr. Brown, Stuart Kornfeld will serve as his primary mentor with continued support from Jason Mills (Co-Mentor). Together, the candidate will be uniquely positioned to acquire the knowledge and skill set necessary to develop an independent research program investigating how specific glycosylation epitopes modulate tissue transformation and differentiation states in metaplasia and cancer. The expression and secretion of sulfomucins is uniformly present in Barrett’s esophagus and esophageal cancer, is the defining feature of type III [high-risk] gastric intestinal metaplasia, and is currently the best biomarker for detecting high-grade dysplasia and cancer in pancreatic cystic lesions. Using a comprehensive approach involving cell lines, organoid culture, and murine models, the experiments proposed herein will determine the proteome carrying 3’-Sulfo-LeA/C, the cellular signaling and transcriptional profile regulating its synthesis and secretion, as well as the molecular mechanism by which specific galectins modulate cellular differentiation. Ultimately, with the mentorship provided by Stuart Kornfeld, Jason Mills, and the research advisory committee, the knowledge and technical skills derived from the proposed experiments, and completion of the outlined career development plan, Dr. Brown will be well-prepared to establish an independent research program and is expected to be highly-competitive for R01 funding.

项目摘要 /摘要 该申请提出了一项为期五年的研究职业发展计划，旨在确定如何 在化生和癌症期间表达的糖基化表位有助于这些临床上重要的细胞 转型。申请人Jeffrey W. Brown，M.D。 华盛顿大学医学院的胃肠病学。自完成胃肠病学研究金以来 布朗博士曾在杰森·米尔斯（Jason Mills）的实验室工作，在那里他发现了一个新颖的细胞过程 调用catartototosis [希腊：细胞清洁]，该细胞被用来有效地推导 化生和癌症的过程。随后，他确定了s脑细胞增多症。 Glycan 3'-sulfo-lea/c和小鼠无效的半乳糖蛋白，优先绑定此插曲无法执行 颗粒细胞增多症或未能将磺肌蛋白包装到成熟的颗粒中。由于糖生物学是布朗博士的新领域 斯图尔特·科恩菲尔德（Stuart Kornfeld）将在杰森·米尔斯（Jason Mills（Co-Insor））的持续支持下作为他的主要精神。一起， 候选人将是独特的位置，以获取开发必要的知识和技能 独立研究计划研究了特定糖基化表位如何调节组织转化 和化生和癌症中的分化状态。 亚磺辛蛋白的表达和分泌在巴雷特的食管和食管中均匀地呈现 癌症是III型[高风险]胃肠化生的定义特征，目前是最好的 用于检测胰腺囊性病变中高级发育不良和癌症的生物标志物。使用全面 涉及细胞系，器官培养和鼠模型的方法，本文提出的实验将 确定携带3'-硫叶/C的蛋白质组，细胞信号传导和转录曲线调节其 合成和分泌，以及特异性半乳糖素调节细胞的分子机制 分化。最终，随着斯图尔特·科恩菲尔德（Stuart Kornfeld），杰森·米尔斯（Jason Mills）和研究的指导 咨询委员会，拟议实验的知识和技术技能以及完成 在概述的职业发展计划中，布朗博士将准备好建立独立研究 计划，预计将对R01资金高度竞争。