Elucidation of the molecular mechanism of CBWD1 in the kidney development

• Project/Area Number: 20K08584
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Kanda Shoichiro 東京大学, 医学部附属病院, 講師 (60632651)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: CBWD1 / 尿管芽 / 腎臓発生 / 先天性腎尿路異常 / CAKUT / Cbwd1

Outline of Research at the Start

CAKUTの新規原因遺伝子であるCBWD1がどのようなメカニズムで腎臓発生に寄与しているか、解明する。ノックアウトマウスを用いたRNA-seqや胎仔腎を用いたin vivoでのChIP-seqを組み合わせ、CBWD1の下流で制御される分子ネットワークを明らかにする。また実際のCAKUT患者におけるCBWD1遺伝子異常の頻度も明らかにする。

Outline of Final Research Achievements

CBWD1 is a novel causative gene for CAKUT discovered by the applicant (Kanda S, et al. Journal of the American Society of Nephrology, 2020). In this study, we analyzed how CBWD1 is involved in kidney development.
Since CBWD1 is expressed in ureteric buds, we evaluated changes in Ret expression, but no changes in expression levels were observed in Cbwd1-knockout mice. Next, RNA-seq analysis was performed using CBWD1 knockout mouse embryonic kidney. Sixty-five genes whose expression level was changed by Cbwd1 knockout were confirmed.

Academic Significance and Societal Importance of the Research Achievements

CBWD1の腎臓発生における役割を明らかにすることを目的に研究を行った。CBWD1ノックアウトにより発生期腎臓で発現量が変動する遺伝子群を見出した点は新規性がある。しかし、これらの遺伝子群の腎臓発生への関わりは明らかにできなかったので、この点は今後の課題である。
一方、CBWD1に関する申請者が執筆した論文（Kanda S, et al. Journal of the American Society of Nephrology, 2020）が他の論文から引用されたり、CBWD1に関する他の研究報告がされたりするようになったことはCBWD1に関係する研究の先駆けとして社会的意義があったと言える。

Research Products

• [Journal Article] Circulating nephrin autoantibodies and post‐transplant recurrence of primary focal segmental glomerulosclerosis (2022)
  • Author(s): Hattori Motoshi、Shirai Yoko、Kanda Shoichiro、Ishizuka Kiyonobu、Kaneko Naoto、Ando Taro、Eguchi Makoto、Miura Kenichiro
  • Journal Title: American Journal of Transplantation Volume: 未定 Issue: 10 Pages: 2478-2480
  • DOI: 10.1111/ajt.17077
  • Peer Reviewed / Open Access
• [Journal Article] Precise clinicopathologic findings for application of genetic testing in pediatric kidney transplant recipients with focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome (2022)
  • Author(s): Miura Kenichiro、Kaneko Naoto、Hashimoto Taeko、Ishizuka Kiyonobu、Shirai Yoko、Hisano Masataka、Chikamoto Hiroko、Akioka Yuko、Kanda Shoichiro、Harita Yutaka、Yamamoto Toshiyuki、Hattori Motoshi
  • Journal Title: Pediatric Nephrology Volume: 38 Issue: 2 Pages: 417-429
  • DOI: 10.1007/s00467-022-05604-3
  • Peer Reviewed
• [Journal Article] A case of right hypodysplastic kidney and ectopic ureter associated with bicornuate uterus in a prepubertal girl (2022)
  • Author(s): Nakamura Misako、Kanda Shoichiro、Kajiho Yuko、Hinata Munetoshi、Tomonaga Kotaro、Fujishiro Jun、Harita Yutaka
  • Journal Title: CEN Case Reports Volume: 12 Issue: 1 Pages: 122-129
  • DOI: 10.1007/s13730-022-00730-1
  • Peer Reviewed
• [Journal Article] Urinary extracellular vesicles signature for diagnosis of kidney disease (2022)
  • Author(s): Takizawa Keiichi、Ueda Koji、Sekiguchi Masahiro、Nakano Eiji、Nishimura Tatsuya、Kajiho Yuko、Kanda Shoichiro、Miura Kenichiro、Hattori Motoshi、Hashimoto Junya、Hamasaki Yuko、Hisano Masataka、Omori Tae、Okamoto Takayuki、Kitayama Hirotsugu、Fujita Naoya、Kuramochi Hiromi、Ichiki Takanori、Oka Akira、Harita Yutaka
  • Journal Title: iScience Volume: 25 Issue: 11 Pages: 105416-105416
  • DOI: 10.1016/j.isci.2022.105416
  • Peer Reviewed / Open Access
• [Journal Article] 腹膜刺激症状を伴う腹痛を初発症状とした不全型川崎病および既報例のまとめ. (2022)
  • Author(s): 北岡寛己, 梶保祐子, 大和田啓峰, 大橋瑛梨, 高橋千恵, 神田祥一郎, 張田豊, 岡明.
  • Journal Title: 日本小児科学会雑誌 Volume: 126 Pages: 1287-1297
  • Peer Reviewed
• [Journal Article] 重症貧血を伴う心不全の原因検索中に判明した自己瀉血. (2022)
  • Author(s): 平野瑶子, 絹巻暁子, 梶保祐子, 高橋千恵, 神田祥一郎, 加藤元博.
  • Journal Title: 日本小児科学会雑誌 Volume: 126 Pages: 1505-1511
  • Peer Reviewed
• [Journal Article] 呼吸障害を契機に診断されたダンベル型甲状舌管嚢胞の2ヵ月女児. (2022)
  • Author(s): 入江紗瑛子, 絹巻暁子, 田中裕之, 高橋千恵, 大和田啓峰, 梶保祐子, 神田祥一郎, 前澤身江子, 松井彦郎, 張田豊.
  • Journal Title: 小児科臨床 Volume: 75 Pages: 1001-1005
  • Peer Reviewed
• [Journal Article] A case of early onset cystinuria in a 4-month-old girl. (2022)
  • Author(s): Ikeyama S, Kanda S, Sakamoto S, Sakoda A, Miura K, Yoneda R, Nogi A, Ariji S, Shimoda M, Ono M, Kanda S, Yokoyama S, Takahashi K, Yokoyama Y, Hattori M
  • Journal Title: CEN Case Rep Volume: 11 Issue: 2 Pages: 216-219
  • DOI: 10.1007/s13730-021-00655-1
  • Peer Reviewed / Open Access
• [Journal Article] A novel de novo truncating TRIM8 variant associated with childhood-onset focal segmental glomerulosclerosis without epileptic encephalopathy: a case report (2021)
  • Author(s): Shirai Yoko、Miura Kenichiro、Kaneko Naoto、Ishizuka Kiyonobu、Endo Amane、Hashimoto Taeko、Kanda Shoichiro、Harita Yutaka、Hattori Motoshi
  • Journal Title: BMC Nephrology Volume: 22 Issue: 1 Pages: 417-417
  • DOI: 10.1186/s12882-021-02626-1
  • NAID: 120007181370
  • Peer Reviewed / Open Access
• [Journal Article] An infant with X-linked anhidrotic ectodermal dysplasia with immunodeficiency presenting with Pneumocystis pneumonia: A case report. (2021)
  • Author(s): Toyohara M, Kajiho Y, Toyofuku E, Takahashi C, Owada K, Kanda S, Harita Y, Ohnishi H, Wada T, Imai K, Kanegane H, Morio T, Oka A
  • Journal Title: Clin Case Rep Volume: 9 Issue: 11
  • DOI: 10.1002/ccr3.5093
  • Peer Reviewed / Open Access
• [Journal Article] Cancer After Pediatric Kidney Transplantation: A Long-term Single-center Experience in Japan (2021)
  • Author(s): Yabuuchi Tomoo, Miura Kenichiro, Shimizu Satoru, Kaneko Naoto, Ishizuka Kiyonobu, Kanda Sshoichiro, Chikamoto Hiroko, Akioka Yuko, Fujieda Mikiya, Hattori Motoshi
  • Journal Title: Transplantation Direct Volume: 7 Issue: 4 Pages: e687-e687
  • DOI: 10.1097/txd.0000000000001137
  • NAID: 120007183297
  • Peer Reviewed / Open Access
• [Journal Article] Combination therapy of continuous nebulization and high-flow nasal cannula for severe congenital tracheal stenosis. (2021)
  • Author(s): Ota H, Kanda S, Uchida K, Hayashi K, Maezawa M, Matsui H
  • Journal Title: Pediatr Pulmonol Volume: 56 Issue: 12 Pages: 455-4056
  • DOI: 10.1002/ppul.25670
  • Peer Reviewed
• [Journal Article] Response to steroid and immunosuppressive therapies may predict post‐transplant recurrence of steroid‐resistant nephrotic syndrome (2021)
  • Author(s): Miura Kenichiro、Ando Taro、Kanda Shoichiro、Hashimoto Taeko、Kaneko Naoto、Ishizuka Kiyonobu、Hamada Riku、Hataya Hiroshi、Hotta Kiyohiko、Gotoh Yoshimitsu、Nishiyama Kei、Hamasaki Yuko、Shishido Seiichiro、Fujita Naoya、Hattori Motoshi
  • Journal Title: Pediatric Transplantation Volume: - Issue: 8 Pages: 14103-14103
  • DOI: 10.1111/petr.14103
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A case of 17q12 deletion syndrome that presented antenatally with markedly enlarged kidneys and clinically mimicked autosomal recessive polycystic kidney disease (2021)
  • Author(s): Nakamura Misako、Kanda Shoichiro、Kajiho Yuko、Morisada Naoya、Iijima Kazumoto、Harita Yutaka
  • Journal Title: CEN Case Reports Volume: 10 Issue: 4 Pages: 543-548
  • DOI: 10.1007/s13730-021-00604-y
  • Peer Reviewed / Open Access
• [Journal Article] Rituximab-induced serum sickness in a 6-year-old boy with steroid-dependent nephrotic syndrome. (2020)
  • Author(s): Nakamura M, Kanda S, Yoshioka Y, Takahashi C, Owada K, Kajiho Y, Harita Y, Oka A
  • Journal Title: CEN Case Rep Volume: 9 Issue: 2 Pages: 173-176
  • DOI: 10.1007/s13730-020-00449-x
  • Peer Reviewed
• [Journal Article] Deletion in the cobalamin synthetase W domain-containing protein 1 gene is associated with congenital anomalies of the kidney and urinary tract. (2020)
  • Author(s): Kanda S, Ohmuraya M, Akagawa H, Horita S, Yoshida Y, Kaneko N, Sugawara N, Ishizuka K, Miura K, Harita Y, Yamamoto T, Oka A, Araki K, Furukawa T, Hattori M.
  • Journal Title: J Am Soc Nephrol Volume: 31 Issue: 1 Pages: 139-147
  • DOI: 10.1681/asn.2019040398
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of an Exon Skipping Therapy for X-linked Alport Syndrome With Truncating Variants in COL4A5. (2020)
  • Author(s): Yamamura T, Horinouchi T, Adachi T, Terakawa M, Takaoka Y, Omachi K, Takasato M, Takaishi K, Shoji T, Onishi Y, Kanazawa Y, Koizumi M, Tomono Y, Sugano S, Shono A, Minamikawa S, Nagano C, Sakakibara N, Ishiko S, Aoto Y, Kamura M, Harita Y, Miura K, Kanda S, Morisada N, and 6 others.
  • Journal Title: Nat Commun . Volume: 11(1) Issue: 1 Pages: 2777-2777
  • DOI: 10.1038/s41467-020-16605-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The cellular model of albumin endocytosis uncovers link between membrane and nuclear proteins (2020)
  • Author(s): Urae Seiya、Harita Yutaka、Udagawa Tomohiro、Ode Koji L.、Nagahama Masami、Kajiho Yuko、Kanda Shoichiro、Saito Akihiko、Ueda Hiroki R.、Nangaku Masaomi、Oka Akira
  • Journal Title: Journal of Cell Science Volume: - Issue: 13
  • DOI: 10.1242/jcs.242859
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Incomplete cryptic splicing by an intronic mutation of OCRL in patients with partial phenotypes of Lowe syndrome (2020)
  • Author(s): Nakano Eiji、Yoshida Amine、Miyama Yudai、Yabuuchi Tomoo、Kajiho Yuko、Kanda Shoichiro、Miura Kenichiro、Oka Akira、Harita Yutaka
  • Journal Title: Journal of Human Genetics Volume: 65 Issue: 10 Pages: 831-839
  • DOI: 10.1038/s10038-020-0773-3
  • Peer Reviewed
• [Journal Article] Renal hypoplasia can be the cause of membranous nephropathy-like lesions. (2020)
  • Author(s): Keiichi Takizawa, Kenichiro Miura, Naoto Kaneko, Tomoo Yabuuchi, Kiyonobu Ishizuka, Shoichiro Kanda, Yutaka Harita, Yuko Akioka, Shigeru Horita, Sekiko Taneda, Kazuho Honda, Motoshi Hattori
  • Journal Title: Clin Exp Nephrol Volume: 24 Issue: 9 Pages: 813-820
  • DOI: 10.1007/s10157-020-01902-y
  • Peer Reviewed / Open Access
• [Journal Article] 学校検尿を契機に診断されたPKHD1遺伝子変異を有する多発性嚢胞腎の1例 (2020)
  • Author(s): 森口駿, 神田祥一郎, 森貞直哉, 梶保祐子, 張田豊, 飯島一誠, 岡明
  • Journal Title: 小児科臨床 Volume: 73 Pages: 1316-1320
  • Peer Reviewed
• [Journal Article] CBWD1欠失によるCAKUT (2020)
  • Author(s): 吉田賢弘, 神田祥一郎
  • Journal Title: 発達腎研究会誌 Volume: 28 Pages: 41-43
• [Journal Article] 先天性腎尿路異常の新規原因遺伝子の探索 CBWD1の腎発生における役割の解明. (2020)
  • Author(s): 神田祥一郎, 大村谷昌樹, 赤川浩之, 堀田茂, 吉田賢弘, 金子直人, 菅原典子, 石塚喜世伸, 三浦健一郎, 張田豊, 山本俊至, 岡明, 荒木喜美, 古川徹, 服部元史
  • Journal Title: 日本透析医会雑誌 Volume: 35 Pages: 189-193
• [Journal Article] 先天性腎尿路異常発症の理解のために－新規原因遺伝子CBWD1の発見. (2020)
  • Author(s): 神田祥一郎, 服部元史
  • Journal Title: 医学のあゆみ Volume: 275 Pages: 902-903
• [Journal Article] 序文 小児科医の将来を考える - あなたは10年後のあなたと向き合えますか (2020)
  • Author(s): 神田祥一郎
  • Journal Title: 小児科診療 Volume: 83 Pages: 987-987
• [Journal Article] どんな小児科医になりたい？ 大学病院では？ (2020)
  • Author(s): 神田祥一郎
  • Journal Title: 小児科診療 Volume: 83 Pages: 991-995
• [Journal Article] 発生の障害による奇形（異形成や低形成） (2020)
  • Author(s): 神田祥一郎
  • Journal Title: 腎と透析 Volume: 89 Pages: 295-300
• [Presentation] Physician-Scientistとしての研究のすすめ ～研究を志す若者へ～ (2022)
  • Author(s): 神田祥一郎
  • Organizer: 第57回日本小児腎臓病学会学術集会
  • Invited
• [Presentation] 腎臓発生から考えるCAKUTの基礎と臨床. (2022)
  • Author(s): 神田祥一郎
  • Organizer: 第30回発達腎研究会
  • Invited
• [Presentation] 疾患レクチャー（ネフロン癆） (2022)
  • Author(s): 神田祥一郎
  • Organizer: 第52回日本腎臓学会東部学術大会
• [Presentation] 遺伝子診断を診療にどう生かすか. (2022)
  • Author(s): 神田祥一郎
  • Organizer: 第43回日本小児腎不全学会学術集会
• [Remarks] 先天性腎尿路異常の新規原因遺伝子を発見
  • URL: https://www.h.u-tokyo.ac.jp/participants/research/saishinkenkyu/20200110