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Initiation and regulation of mucin-type O-glycosylation

粘蛋白型O-糖基化的启动和调节

基本信息

批准号：
9012950
负责人：
THOMAS A GERKEN
金额：
$ 15.74万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9012950
关键词：
Accounting Address Animal Model Animals Belief Benign Biological Biological Process Biology C-terminal Cardiovascular Diseases Cardiovascular system Cell Communication Cell Culture Techniques Cell Line Cells Complement Data Development Disease Embryonic Development Enzymatic Biochemistry Enzymes Family Fertility Functional disorder Glycopeptides Goals Health Hormonal Host Defense Human In Vitro Individual Inflammatory Institution Kinetics Knock-out Lead Learning Libraries Link Malignant Neoplasms Membrane Metabolic Methods Modification Molecular Mucins Mus Mutation Online Systems Pattern Peptides Play Polypeptide N-acetylgalactosaminyltransferase Polysaccharides Prevalence Process Property Protein Glycosylation Protein Isoforms Proteins Regulation Reporting Reproduction Role Series Site Specificity Structure Substrate Specificity Therapeutic Tissues Transferase Work animal tissue base design fly glycosylation in vivo inhibitor/antagonist innovation male man member neoplastic novel novel strategies polypeptide ppGalNAc-T predictive modeling preference public health relevance sugar therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Most membrane and secreted proteins are decorated with mucin-type O-glycans which serve diverse biological roles. The mechanisms behind their biological roles and more specifically what governs O-glycan site selection and subsequent O-glycan elongation are largely unknown. The objective of this project is to elucidate the processes governing O-glycan site selection and O-glycan elongation at the enzyme and peptide substrate level in order to address the molecular mechanisms and biology of O-glycosylation. Mucin type O- glycosylation is vital to animal reproduction and development and increasingly linked to a wide range of rare to common disease states (such as hormonal/metabolic dysfunction, impaired host defense, inflammatory and cardiovascular diseases and even cancers) where it serves to modulate diverse biological functions including cell-cell interactions. Many disorders are linked to changes in expression or mutation of individual members of the large family (20 in man) of polypeptide-GalNAc transferases (ppGalNAc Ts) that initiate O-glycosylation by adding GalNAc to polypeptide Ser or Thr residues. O-glycosylation is absolutely required for embryonic development of the mouse and fly, relying on the Core 1 elongating transferase (T-synthase) in the mouse and several individual ppGalNAc T isoforms in the fly. How individual ppGalNAc T isoforms in this large family (or even T-synthase) can play such critical biological roles is unknown as the substrate specificity of these transferases have not been sufficiently characterized. That ppGalNAc T site selection is also modulated (positively or negatively) by prior glycosylation underscores its complexity and how much more needs to be learned of its specificity. The detailed characterization of ppGalNAc T isoform and elongating transferase specificity proposed in this project will lead to our understanding of the molecular mechanisms underlying the biological roles of O-glycosylation and will eventually lead to novel strategies to treat diseases of aberrant O- glycosylation. The AIMS of this project are to (1) expand the innovative use of a library of novel random peptide and glycopeptide substrates to fully characterize the specificity and basic enzymology of the transferases that initiate and elongate mucin type O-glycosylation, (2) to use these data to further develop sophisticated web based O-glycan predictive tools that include ppGalNAc T isoform and elongating transferase peptide and glycopeptide specificity, and (3) to develop a novel method for identifying in vivo isoform specific glycosylation targets using tissues from transferase knock-out animal models. These basic studies together with those of colleagues at other institutions will advance our understanding of the properties of these transferases, their targets (and resultant glycan structures) and ultimately the mechanisms of their biological role and function. These studies will significantly advance the field and will allw the development of novel specific inhibitors for potential use as targeted therapeutics.