Neoglycosylation Epitopes in Metaplasia and Cancer

化生和癌症中的新糖基化表位

• 批准号: 10597216
• 负责人: Jeffrey Wade Brown
• 金额: $ 16.51万
• 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/10597216
• 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; Knowledge acquisition; 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; progression risk; protein transport; segregation; 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.

项目总结/摘要 这项申请提出了一个为期五年的研究职业发展计划，重点是确定如何 在化生和癌症期间表达的糖基化表位有助于这些临床上显著的细胞凋亡。 转变申请人Jeffrey W.布朗，医学博士，哲学博士、是一个医学导师在司 华盛顿大学医学院胃肠病学。自从完成胃肠病学奖学金， 博士布朗曾在杰森米尔斯的实验室工作，在那里他发现了一种新的细胞过程，他 称为cathartocytosis [希腊语：细胞净化]，细胞利用它来有效地去分化， 化生和癌症的过程。他随后确定，胞吐作用是由 聚糖3 '-磺基-LeA/C和缺乏优先结合该表位的半乳糖凝集素的小鼠， 胞吐作用或不能将磺粘蛋白包装成成熟颗粒。由于糖生物学对布朗博士来说是一个新领域， Stuart Kornfeld将担任他的主要导师，并得到Jason米尔斯（联合导师）的持续支持。我们一起努力， 候选人将处于独特的地位，以获得必要的知识和技能，以发展 独立研究计划调查特定糖基化表位如何调节组织转化 以及化生和癌症中的分化状态。 硫粘蛋白的表达和分泌均匀地存在于Barrett食管和食管癌中。 癌症，是III型[高危]胃肠道化生的定义特征，是目前最好的 用于检测胰腺囊性病变中高度异型增生和癌症的生物标志物。使用一个全面的 涉及细胞系、类器官培养物和鼠模型的方法，本文提出的实验将 确定携带3 '-Sulfo-LeA/C的蛋白质组，调节其的细胞信号传导和转录谱， 合成和分泌，以及特异性半乳糖凝集素调节细胞的分子机制， 分化最终，在Stuart Kornfeld和Jason米尔斯的指导下， 咨询委员会，从拟议的实验中获得的知识和技术技能，以及完成 在概述的职业发展计划中，布朗博士将为建立一个独立的研究机构做好充分的准备。 计划，并预计将是高度竞争的R 01资金。