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Objective and necessity of the study
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With the advancement of genome projects, analyses of various biomolecules and biomolecular interactions have become realistic and essential research themes leading to a true understanding of the life process. In addition to studies focused on proteins and nucleic acids, sugars and lipids, even though they are not direct gene products, must also be studied as biological regulators. Their importance is becoming more and more recognized. Isolation of glycosylation enzyme genes of glycoconjugates such as glycoproteins, glycolipids and proteoglycans has been mostly completed in the past 10 years, making it possible to specifically and extensively analyze the physiology of sugar chains contained in these molecules. The dramatic development of sugar chain gene analysis and rapid advancement of genomics have raising expectations for new developments in Glycobiology. The elucidation of the regulatory roles of glycoconjugates in proteins and molecular complexes, the indirect gene products, is now considered to be an essential project in postgenomics as well as an indispensable research field for clarifying molecular mechanisms in a variety of biological phenomena. In light of the structural characteristics of sugar chains and their cross-sectional significance in biodynamics, we developed a research plan based on our belief that a research field called Functional Glycomics is needed to be established.
The completed cloning of glycosylation-related genes and the results of various experiments using genetic engineering techniques at the cellular and individual levels suggest that sugar chains are deeply involved in fundamental life processes such as development, differentiation, proliferation, apoptosis and cancer. Examples include deletion of a sulfation enzyme gene in heparan sulfate leading to kidney aplasia, deletion of complex acidic glycolipids leading to aspermatogenesis, arrested triploblastic development leading to embryonic death in animals with defective synthesis of glycolipid, and the disappearance of cytotoxic T-cells (CD8+) by apoptosis in mice without sialylation of the O-sugar chain. On the other hand, human diseases and clinical conditions associated with abnormal sugar chains or abnormality in their modification enzyme genes including enzyme mutation in the N-sugar chain synthetic pathway in a group of congenital diseases called congenital disorders of glycosylation (CDG), mutation of a synthase of the heparan sulfate sugar chain identified as the causative gene of the familial exostosis, mutation of the glycosaminoglycan sugar chain synthase identified in progeroid type of Ehlers-Danlos syndrome, and mutation of fucosyltransferase detected in patients with immune abnormalities, have been identified.
However, how these functional aberrations of glycosylation-related genes cause abnormal phenotypes and lead to pathologic conditions remain unclear. Most of the target molecules glycosylated by individual enzymes in the important process of posttranslational modification of proteins have not been analyzed. Glycosylation of proteoglycans or glycolipids, changes in sugar chain plofiles associated with modification, and functions and structures of molecular complexes that encompass these phenomena are mostly unknown.
The development of Functional Glycomics must be positioned as the most important and essential research in postgenome science. Since more than 50% of all proteins are glycosylated to function, specific advancement of proteomics research can not be achieved without sugar chain analysis. Elucidation of the functions of glycosylation-related and proteoglycans is essentially the analysis of sugar chain functions. Glycobiology has advanced from the chemical analysis of carbohydrate structures to the cloning of glycosylation-related genes and genetic remodeling of glycosylation-related. For the advancement of such Glycobiology in the 21st century, we aim to elucidate the molecular functions of sugar chains by establishing a new research paradigm in which molecular biology, glycotechnology and structural biology are integrated.
The study will be conducted by three groups of researchers under the following themes:
(1) Functional regulation of proteins by sugar chains
(2) Functional regulation of molecular complexes by sugar chains
(3) Molecular mechanisms for diseases derived from aberrant Glycosylation
Japanese glycoscientists have been involved in the cloning of more than half of genes of glycosylation-related enzymes and lead the Glycobiology field at the international level.
They have analyzed carbohydrate functions by genetic engineering, created a variety of mouse disease models, and elucidated diseases and pathologic conditions associated with glycosylation abnormality. Based on their experiences, we will aim for further advances in this cutting-edge research project. Prospective study results will no doubt have tremendous spillover effects on other research fields and are expected to be a major factor for advancement of life science as a whole.
Outline of the Grant-in-Aid for Scientific Research of Priority Areas "Functional Regulation of Proteins and Molecular Complexes by Sugar Chains"
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