The analysis of pathogensis and therapy deveolpment of kidney involvement of monoclonal kappa chain-induced crystal-storing histiocytosis

Research Project

Project/Area Number	16K19485
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Kidney internal medicine
Research Institution	Kanazawa University
Principal Investigator	Hara Satoshi 金沢大学, 医学系, 助教 (80749820)
Project Period (FY)	2016-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000) Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000) Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywords	ポドサイト / 軽鎖 / 発現ベクター / トランスジェニックマウス / マクロファージ / 内科 / 病理学 / 蛋白質 / 臨床
Outline of Final Research Achievements	We identified the pathogenic kappa light chain causing crystal-storing histiocytosis and succeeded in producing huge amount of the protein. We confirmed that this pathogenic kappa light chain was endocytosed and crystalized in mice macrophages, podocytes, and proximal tubular cells in vitro. However, we did not determine how the light chain has its toxicity for those cells and the mechanism of kappa light chain integration into those cells. We created transgenic mice which secrete the pathogenic kappa light chain. The transgenic mice formed macrophages containing kappa crystals in spleen, but did not show any kidney involvements of crystal-storing histiocytosis due to small amount of pathogenic kappa light chain secretion.
Academic Significance and Societal Importance of the Research Achievements	マクロファージや近位尿細管のみならず、ポドサイトにも結晶を形成しうる変異軽鎖の配列を同定し、その蛋白精製を行うことができた。今後これを用いて、ポドサイトへの取り込み機序の解明を行うことで、軽鎖によるポドサイト障害の機序ひいては慢性腎臓病の機序解明と治療薬開発へつながる可能性がある。