High-throughput verification of pathways regulating kidney diseases

• Project/Area Number: 19K22628
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Tokai University
• Principal Investigator: MATSUSAKA Taiji 東海大学, 医学部, 教授 (50317749)
• Co-Investigator(Kenkyū-buntansha): 梅津 光央 東北大学, 工学研究科, 教授 (70333846)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 腎臓病 / 低分子抗体 / ポドサイト / ガイドRNA / 遺伝子改変

Outline of Research at the Start

腎臓病は、透析治療を必要とする腎不全の原因となる大きな問題である。腎臓病の鍵をにぎるのは、タコ足細胞の傷害である。タコ足細胞は、腎全体の1%足らずの少数ではあるが、文字通りタコのように突起を伸ばし、尿に蛋白を漏らさない働きをしている。本研究では、マウスのタコ足細胞に効率よく簡便に遺伝子を変異させる方法を開発し、変異により傷害を軽くする遺伝子を探す事をめざしている。将来的にこの研究は、タコ足細胞の治療薬の開発へとつながる事が期待される。

Outline of Final Research Achievements

Gene expression pattern is dynamically changed in kidney diseases. To study gene functions in kidney diseases, we aimed to develop a simple method to modify a specific gene in a mouse body with kidney disease. We generated mice in which the kidney expresses a gene-modifying enzyme and tried to develop a carrier protein that delivers guide RNA to kidney cells. The carrier protein is taken up into kidney cells, however further improvement is necessary to accomplish this project.

Academic Significance and Societal Importance of the Research Achievements

期間内に達成できなかったが、核酸を特定の細胞に送り込む技術は、医学生物学研究を加速させる基盤技術となるし、治療薬としての利用が注目されている核酸の腎臓への送達技術は、臨床的にも重要である。今研究で明らかになった技術的問題の解決が望まれる。

Research Products

• [Journal Article] Global polysome analysis of normal and injured podocytes (2019)
  • Author(s): Okabe Masahiro, Motojima Masaru, Miyazaki Yoich, Pastan Ira, Yokoo Takashi, Matsusaka Taiji
  • Journal Title: American Journal of Physiology-Renal Physiology Volume: 316 Issue: 2 Pages: F241-F252
  • DOI: 10.1152/ajprenal.00115.2018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proximal Tubule Autophagy Differs in Type 1 and 2 Diabetes (2019)
  • Author(s): Sakai S, Yamamoto T, Takabatake Y, Takahashi A, Namba-Hamano T, Minami S, Fujimura R, Yonishi H, Matsuda J, Hesaka A, Matsui I, Matsusaka T, Niimura F, Yanagita M, Isaka Y.
  • Journal Title: J Am Soc Nephrol Volume: 30(6) Issue: 6 Pages: 929-945
  • DOI: 10.1681/asn.2018100983
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Possible role of complement factor H in podocytes in clearing glomerular subendothelial immune complex deposits (2019)
  • Author(s): Zoshima T, Hara S, Yamagishi M, Pastan I, Matsusaka T, Kawano M, Nagata M.
  • Journal Title: Sci Rep Volume: 9(1) Issue: 1 Pages: 7857-7857
  • DOI: 10.1038/s41598-019-44380-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Podocyte Injury Augments Intrarenal Angiotensin II Generation and Sodium Retention in a Megalin-Dependent Manner (2019)
  • Author(s): Koizumi Masahiro、Ueda Kohei、Niimura Fumio、Nishiyama Akira、Yanagita Motoko、Saito Akihiko、Pastan Ira、Fujita Toshiro、Fukagawa Masafumi、Matsusaka Taiji
  • Journal Title: Hypertension Volume: 74 Issue: 3 Pages: 509-517
  • DOI: 10.1161/hypertensionaha.118.12352
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metabolic effects of RUBCN/Rubicon deficiency in kidney proximal tubular epithelial cells (2019)
  • Author(s): Matsuda J, Takahashi A, Takabatake Y, Sakai S, Minami S, Yamamoto T, Fujimura R, Namba-Hamano T, Yonishi H, Nakamura J, Kimura T, Kaimori JY, Matsui I, Takahashi M, Nakao M, Izumi Y, Bamba T, Matsusaka T, Niimura F, Yanagita M, Yoshimori T, Isaka Y.
  • Journal Title: Autophagy Volume: - Pages: 1-16
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autophagy protects kidney from phosphate-induced mitochondrial injury (2019)
  • Author(s): Fujimura R, Yamamoto T, Takabatake Y, Takahashi A, Namba-Hamano T, Minami S, Sakai S, Matsuda J, Hesaka A, Yonishi H, Nakamura J, Matsui I, Matsusaka T, Niimura F, Yanagita M, Isaka Y.
  • Journal Title: Biochem Biophys Res Commun Volume: S0006-291X(20) Issue: 3 Pages: 30220-5
  • DOI: 10.1016/j.bbrc.2020.01.137
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biphasic MIF and SDF1 expression during podocyte injury promote CD44-mediated glomerular parietal cell migration in focal segmental glomerulosclerosis (2019)
  • Author(s): Ito N, Sakamoto K, Hikichi C, Matsusaka T, Nagata M.
  • Journal Title: Am J Physiol Renal Physiol Volume: 318(3)
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] P2X7 Expressed in Injured Podocytes May Spread the Kidney Injury Through Caspase 3 (2019)
  • Author(s): Yamamoto Kazuyoshi,Matsusaka Taiji
  • Organizer: ASN Kidney Week
  • Int'l Joint Research
• [Presentation] C-Type Lectin-Like Receptor (CLEC)-2, the Ligand of Podoplanin, Facilitates Motility of Podocytes (2019)
  • Author(s): Tanaka Keiko,Matsusaka Taiji
  • Organizer: ASN Kidney Week
  • Int'l Joint Research
• [Presentation] Kidney Organoid Model of Selective Podocyte Injury (2019)
  • Author(s): UdagawaTomohiro ,Matsusaka Taiji
  • Organizer: ASN Kidney Week
  • Int'l Joint Research
• [Presentation] Angiotensin II Receptor Blocker Blocks Spreading Podocyte Damage in a Partial Podocytectomy Model (2019)
  • Author(s): Okabe Masahiro ,Matsusaka Taiji
  • Organizer: ASN Kidney Week
  • Int'l Joint Research