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.

项目概要/摘要 该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 在化生和癌症过程中表达的糖基化表位有助于这些具有临床意义的细胞 申请人 Jeffrey W. Brown，医学博士，哲学博士，是医学部的医学讲师。 自从完成胃肠病学奖学金以来，华盛顿大学医学院的胃肠病学。 布朗博士曾在杰森米尔斯的实验室工作，在那里他发现了一种新颖的细胞过程 称为细胞净化作用[希腊语：细胞清洁]，细胞利用它来有效地去分化 他随后确定了化生和癌症的过程。 聚糖 3'-Sulfo-LeA/C 和优先结合该表位的半乳糖凝集素无效的小鼠要么无法执行 由于糖生物学对布朗博士来说是一个新领域，因此无法将磺粘蛋白包装成成熟颗粒。 Stuart Kornfeld 将担任他的主要导师，并得到 Jason Mills（共同导师）的持续支持。 候选人将处于独特的地位，能够获得发展所需的知识和技能。 独立研究项目调查特定糖基化表位如何调节组织转化 以及化生和癌症的分化状态。 磺粘蛋白的表达和分泌均匀存在于巴雷特食管和食管 癌症，是 III 型[高危]胃肠化生的定义特征，也是目前最好的 使用综合性的生物标志物检测胰腺囊性病变中的高度不典型增生和癌症。 方法涉及细胞系、类器官培养和小鼠模型，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，以及特定半乳糖凝集素调节细胞的分子机制 最终，在 Stuart Kornfeld、Jason Mills 的指导和研究的帮助下，我们实现了差异化。 咨询委员会、从拟议实验中获得的知识和技术技能以及完成情况 根据概述的职业发展计划，布朗博士将为建立一个独立的研究做好充分准备 计划，预计在 R01 资金方面具有高度竞争力。