Biochemistry

Introduction

Our long-term goal is to provide novel therapeutic cues to treat inflammatory diseases, allergies, metastatic cancer, infectious diseases, and metabolic syndrome by uncovering the roles of glycoconjugates, p57Kip2, and Pin1 in the pathogenesis. Specific research targets are (1) the discovery and optimization of inhibitors of heparanase, a heparan sulfate degrading enzyme, including future clinical applications to the above diseases, (2) p57Kip2 and Pin1 (a phosphorylated peptide-specific prolyl isomerase) as target molecules to prevent metabolic syndromes. 

Glycoconjugates are one of the major constituents in the mammalian body, however, the roles of those molecules in the biological processes have not been fully uncovered. Sulfated glycoconjugates heparan sulfate and heparin interact with many kinds of functional molecules such as extracellular matrix proteins, enzymes, cytokines/chemokines, and viral proteins, thereby participating in our homeostatic and disease processes. Expression and distribution of the glycoconjugates are metabolically regulated by modifying enzymes including heparanase, the only known mammalian endoglycosidase that cleaves heparan sulfate side chains of proteoglycans. We are interested in exploring the roles of heparanase in pathogenesis, also mining small molecules and antibodies that have therapeutic effects on the diseases.

p57Kip2, a cell cycle regulator, inhibits cell proliferation by suppressing of various protein kinases. The p57-null mice showed placentomegaly and abnormal bone development. The p57-/- embryos induced metabolic diseases in their mothers. From these viewpoints, we aim to seek prevention methods against the metabolic diseases of pregnant mothers and neonates.

Pin1 is only prolyl isomerase to catalyze the cis/trans isomerization of phosphorylated proteins. Pin1 overexpression is closely associated with rapid proliferation by stabilization of Cyclin D1. Recently, it has been reported that Pin1 is one of the risk factors for NASH pathogenesis. We aim to search Pin1 inhibitory molecules in functional foods and their components.

Research interests 

Nobuaki Higashi, Ph. D.
– Functional roles of glycosaminoglycans, extracellular matrices, and degradation enzymes in cancer, inflammatory diseases, allergies, and infection  
– Cleavage of carbohydrates as an alert of danger 
– Design of heparanase (glycosidase) inhibitors 

Katsuhiko Takahashi, Ph. D. 
– Cell cycle regulation and carcinogenesis  
– Metabolic diseases related to pregnancy 
– Prevention of metabolic diseases 
– Osteoporosis

TOPへ戻る TOP