Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

本研究は小児慢性炎症疾患における生物学的製剤の需要の著しい増加による医療経済的な問題を解決すべく、寛解達成後の休薬、減量、投与間隔の延長の指針を作成、提唱することで、長期的な副作用のリスクを軽減、回避するとともに、より効率的な治療選択を行うシステムを構築することを目的としている。小児の慢性炎症疾患において生物学的製剤の使用実績が最も多く、保険適用がある製剤数も多い若年性特発性関節炎（JIA）についての検討を行っている。システマティックレビューの結果、全身型JIA、およびリウマトイド因子（RF）陰性のJIA多関節炎型、少関節炎型に関しては寛解達成後の休薬が期待できる一方、RF陽性のJIA多関節炎型に関しては休薬による再燃率が高いことが推定され、患者に不利益が生じないよう、減量や投与間隔の延長、メトトレキサートなど従来型疾患修飾性抗リウマチ薬（csDMARDs)への変更など、治療を継続しながらも医療経済的に効率の良い選択肢も含めて検討する必要があると推察された。抗核抗体陽性、低年齢発症、寛解達成までに要する期間が長いことなど、諸外国における複数のretrospective studyで報告されている休薬後の再燃に関するリスクファクターも存在し、これらの検証に加え、本邦での使用実態による再燃リスクファクターを既存テータから解析し、休薬指標となるバイオマーカーの候補を含めて検討中である。

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Grant amount：\3100000 （ Direct Cost: \3100000 ）

In recent years, podocytes have been shown to play a central role in maintaining the filtration barrier of the glomerulus. Several podocyte-related proteins, such as nephrin and podocin, have been identified and analyzed for their function. To identify novel proteins that work specifically in podocytes, we searched for proteins that interact with podocin. We screened a mouse kidney cDNA library using the yeast two-hybrid system and identified a novel protein. The deduced amino acid sequence of the protein consisted of 306 residues with a molecular weight of 34 kDa. Sequence analysis revealed that the protein does not have a distinct functional motif. Reverse transcription-PCR findings showed that the protein was expressed strongly in the kidney, weakly in the brain and heart. The human ortholog of the protein was identified. Amino acid sequences of the protein is highly conserved between mouse and human (81% identity, 92% similarity). We established stable transformants of NIH3T3 cells that expressed podocin and the novel protein added FLAG epitope. Podocin was co-immunoprecipitated with the novel protein by anti-FLAG antibody. Furthermore, the direct association between podocin and the protein was confirmed by GST pull down assay. Using the yeast two-hybrid system to search for proteins that bind to the novel protein, we obtained the Aha1 (activator of HSP90 ATPase). Aha1 is known to bind to HSP90 (heat shock protein 90) and increase the ATPase activity of HSP90. Recently, it was shown that HSP90 regulates the structure of actin filaments. Actin cytoskeleton plays an important role in maintaining the structure of podocytes. The novel protein identified in this study might recruit HSP90 near podocin through the binding to Aha1 and play some roles for actin cytoskeletal formation.

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