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Principal Investigator: Jennifer J Kohler
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $525,698
Funding agency: National Institute of General Medical Sciences
Summary/abstract
This research program focuses on uncovering the biological roles of glycoconjugates. Part of this effort is
devoted to the development of chemical biology tools for glycoscience research. In the past, we have developed
photocrosslinking sugar analogs that can be incorporated into cellular glycoconjugates and used to covalently
crosslink glycoconjugates to their binding partners in a native context. These reagents can be used to identify
glycan-dependent binding interactions, and to characterize where and under what conditions that these
interactions occur. Over the next five years, we will further expand the scope of experiments that can be
performed by preparing additional photocrosslinking sugars, developing new methods for their incorporation,
and evaluating their incorporation into additional glycoconjugates. Using one of these photocrosslinking
sugars, we made the unexpected observation that cholera toxin can bind fucosylated glycoconjugates in
addition to its canonical receptor, the ganglioside GM1. Over the next five years, we will determine the
molecular structure of fucosylated glycoconjugates recognized by cholera toxin and characterize their role in
host cell intoxication. These studies are supported by our long-term collaboration with the Yrlid group
(University of Gothenburg) and their expertise in studying cholera disease mechanisms. Our studies of cholera
toxin receptors led us to become interested in the diverse glycoconjugates that line the intestinal and
respiratory epithelia. A CRISPR screen designed to identify genes that modulate cholera toxin binding to cell
surfaces identified a number of candidate genes that may function in the regulation of glycosylation by diverse
mechanisms. Over the next five years, we will characterize novel regulators of glycosylation and determine how
they shape the glycome, modulating glycan features such as polyLacNAc chain length and the degree of
fucosylation. The long-term goal of these studies is to determine how glycan features vary among individuals,
their association with disease states, and their impact on host-microbe interactions.
Terms: <Binding><Biological><Biology><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cancers><Candidate Disease Gene><Candidate Gene><Cell Body><Cell surface><Cells><Chemicals><Cholera><Cholera Enterotoxin CT><Cholera Exotoxin><Cholera Toxin><Choleragen><Collaborations><Communicable Diseases><Development><Disease><Disorder><Epithelium><G(A(2)) Ganglioside><G(M1) Ganglioside><GA(2) Ganglioside><Ganglioside GM1><Genes><Glycans><Glycoconjugates><Goals><Human><Individual><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Intoxication><Length><Macromolecular Structure><Malignant Neoplasms><Malignant Tumor><Mammalian Cell><Metabolic Glycosylation><Methods><Modern Man><Molecular Interaction><Molecular Structure><Monosialosyl Tetraglycosyl Ceramide><Physiology><Polysaccharides><Predisposition><Production><Reagent><Receptor Protein><Regulation><Research><Respiratory Epithelium><Role><Shapes><Structure of respiratory epithelium><Surface><Susceptibility><Universities><airway epithelium><analog><biologic><cholera toxin binding glycoproteins><cholera toxin receptor><choleragen receptor><clustered regularly interspaced short palindromic repeats screen><crosslink><design><designing><developmental><experiment><experimental research><experimental study><experiments><glycosylation><host microbe association><host microbe relationship><host-microbe interactions><host-microbial interactions><host-microorganism interactions><interest><intestinal epithelium><malignancy><neoplasm/cancer><novel><programs><receptor><respiratory tract epithelium><social role><sugar><tool>