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Principal Investigator: Jeffrey Wade Brown
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $165,062
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Advisory Committees><Antigenic Determinants><Assay><Autoregulation><Barrett Esophagus><Barrett Syndrome><Barrett Ulcer><Binding><Binding Determinants><Bioassay><Biological Assay><Biological Markers><Body Tissues><CBP-30><CBP-35><CBP35><Cadherin-1><Cancer Cause><Cancer Etiology><Cancers><Carbohydrate-Binding Protein 35><Career Choice><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Career Path><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Line><Cell Maturation><Cell Physiology><Cell Process><Cell Signaling><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Transformation><Characteristics><Chemical Fractionation><Chief Cell><Columnar Epithelial-Lined Lower Esophagus><Columnar-Lined Esophagus><Cytoplasmic Granules><D-Galactoside-Binding Lectin><Development Plans><Diagnosis><Doctor of Medicine><Doctor of Philosophy><E-Cadherin><Ensure><Epithelial Calcium-Dependent Adhesion Protein><Epithelial-Cadherin><Epitopes><Epsilon-Binding Protein><Esophageal Cancer><Esophagus Cancer><Expression Signature><FRACN><Fellowship><Foregut><Fractionation><Fractionation Radiotherapy><Funding><Galactose Binding Lectin><Galaptins><Galectin 3><Galectins><Gastric Body Cancer><Gastric Cancer><Gastric Cardia Cancer><Gastric Fundus Cancer><Gastric Pylorus Cancer><Gastroenterology><Gene Chips><Gene Deletion><Gene Expression Chip><Gene Expression Profile><Gene Transcription><GeneChip><Genes><Genetic Models><Genetic Transcription><Glean><Glycans><Glycobiology><Goals><Greek><HL-29><High grade dysplasia><Homeostasis><IgE Binding Protein><IgEBP><Immuno-Electron Microscopy><Immunoelectron Microscopy><Immunofluorescence><Immunofluorescence Immunologic><In Vitro><Intestinal Metaplasia><Intestinal metaplasia of the stomach><Intracellular Communication and Signaling><Investigators><K-Awards><K-Series Research Career Programs><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Knowledge acquisition><L-29 Lectin><L-31><L-34><L30 Lectin><LGALS3><LS174-T><LS174T><LS174T colon cancer cell line><Label><Laboratories><Lysosomes><M.D.><Mac-2 Antigen><Macrophage-2 Antigen><Malignant Esophageal Neoplasm><Malignant Esophageal Tumor><Malignant Gastric Neoplasm><Malignant Gastric Tumor><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Esophagus><Malignant neoplasm of esophagus><Mediating><Medicine><Membrane><Mentors><Mentorship><Metabolic Glycosylation><Metaplasia><Metaplastic Cell><Metaplastic Change><Mice><Mice Mammals><Molecular><Molecular Interaction><Monitor><Mucins><Mucus Glycoprotein><Murine><Mus><N-Acetylneuraminic Acids><Null Mouse><Oncogenesis><Oncogenic><Organoids><Pancreatic cystic neoplasia><Ph.D.><PhD><Phenotype><Physiological Homeostasis><Polysaccharides><Position><Positioning Attribute><Primitive foregut structure><Process><Production><Program Development><Protein Trafficking><Proteins><Proteome><RNA Expression><Repression><Research><Research Career Program><Research Personnel><Researchers><Risk><Role><S-Type Lectins><Sialic Acids><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stomach><Stomach Cancer><Strains Cell Lines><Subcellular Process><Sulfate><System><Task Forces><Technical Expertise><Techniques><Tissues><Transcription><Transmission Electron Microscopy><Universities><Uvomorulin><Washington><Work><advisory team><apical membrane><beta-D-Galactosyl-Specific Lectin><beta-Galactoside Binding Lectin><bio-markers><biologic marker><biological signal transduction><biomarker><career aspiration><career development><career interest><career pathway><career track><cell dedifferentiation><cellular differentiation><clinical significance><clinically significant><cultured cell line><esophageal intestinal metaplasia><experiment><experimental research><experimental study><experiments><expression array><gastric><gastric intestinal metaplasia><gastric malignancy><gene deletion mutation><gene expression microarray><gene expression pattern><gene expression signature><glycosylation><granule><high risk><instructor><loss of function><malignancy><malignant stomach neoplasm><malignant stomach tumor><medical college><medical schools><membrane structure><metaplastic cell transformation><mortality><mouse model><murine model><neoplasm/cancer><novel><oesophageal cancer><pancreatic cystic lesions><pancreatic cystic neoplasms><pancreatic cystic tumors><prevent><preventing><programs><progression risk><protein transport><school of medicine><segregation><sialylation><skills><small molecular inhibitor><small molecule inhibitor><social role><stomach fundus cancer><stomach pylorus cancer><success><sulfomucin><technical skills><tool><trafficking><transcriptional profile><transcriptional signature><tumorigenesis>