Study of the metabolic regulation based on the elucidation of molecular function of Klotho family

2014 Fiscal Year Final Research Report

• Project/Area Number: 22229003
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Foundation for Biomedical Research and Innovation
• Principal Investigator: YO-ICHI Nabeshima 公益財団法人先端医療振興財団, その他部局等, その他 (60108024)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: 恒常性 / レクチン / 結晶構造解析 / クロトー / コレステロール代謝 / HNK-1糖鎖

Outline of Final Research Achievements

We studied molecular mechanisms of newly established homeostasis regulation system by analyzing the molecular functions of α-Kl, β-Kl and circulating FGF subfamily. The followings were clarified. 1) Crystal structure analysis of α-Kl and its MD simulation study revealed α-Kl acts as a novel lectin that recognizes 3S-GlcA/HNK-1 sugars. 2) We found novel functions of glycans in protein- protein interaction and in FGF23 signal trasduction. By analyzing the functions of β-Kl we discovered that 3) Robustness of cholesterol metabolism, 4) Decreased body weight in β-Kl KO is not depend on the increased bile acids synthesis, and 5) β-Kl is involved in the regulation of amino acid metabolism. We also found that 6) Calpain1 inhibitor administration improves the aging related phenotypes of α-Kl KO mice, and that 7) α-Kl gradually decreases during aging and reversely correlates with FGF23 levels. Taken together, animal homeostasis regulation mechanisms are intensively clarified.

Free Research Field

分子病態学