Elucidation of pathogenic mechanisms of ichthyosis due to epidermal lipid abnormalities and development of novel therapeutic agents

• Project/Area Number: 18H02832
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Nagoya University
• Principal Investigator: AKIYAMA Masashi 名古屋大学, 医学系研究科, 教授 (60222551)
• Co-Investigator(Kenkyū-buntansha): 室 慶直 名古屋大学, 医学系研究科, 准教授 (80270990) ; 武市 拓也 名古屋大学, 医学系研究科, 講師 (30754931) ; 河野 通浩 秋田大学, 医学系研究科, 教授 (60319324)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 遺伝子 / 脂質 / 角化 / 魚鱗癬 / 表皮 / 皮膚バリア / 表皮脂質 / 魚燐癬

Outline of Final Research Achievements

The results of this research can be summarized in the following three points. (1) Elucidation of etiology for autosomal recessive congenital ichthyosis patients and aggregation of patient information/samples: We have accumulated autosomal recessive congenital ichthyosis patients nationwide and have identified causative gene mutations in a large number of patients. We have collected the patients’ clinical and genetic information together with biological samples. (2) Elucidation of the pathophysiology of autosomal recessive congenital ichthyosis: We have created autosomal recessive congenital ichthyosis model mice in which causative gene mutations are knocked in. We have analyzed the mice to clarify the pathogenic mechanisms of the disease. (3) Development of etiology-targeting treatments for autosomal recessive congenital ichthyosis: Using the above-mentioned model mice, effectiveness of existing agents to autosomal recessive congenital ichthyosis was evaluated.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ゲノム編集技術により、実際の患者での病因遺伝子変異を導入した、真の疾患モデルと言える多系統のノックインマウスを作成するが、この点が大きな学術的意義と言える。さらに、それらのマウスを用いて、表皮脂質異常により魚鱗癬が発症するメカニズムを詳細に解明する点も意義深い。この研究から得られる知見は、魚鱗癬の病態解明に止まらず、人体の恒常性の維持に重要な皮膚角層バリアの形成機序の解明に繋がる。社会的意義としては、本研究の成果として、多くの未診断であった魚鱗癬症例について確定診断、病因の解明がなされた点が挙げられる。

Research Products

• [Journal Article] MEDNIK-like syndrome due to compound heterozygous mutations in AP1B1. (2021)
  • Author(s): Ito Y, Takeichi T, Igari S, Mori T, Ono A, Suyama K, Takeuchi S, Muro Y, Ogi T, Hosoya M, Yamamoto T, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 35 Issue: 5
  • DOI: 10.1111/jdv.17098
  • Peer Reviewed
• [Journal Article] Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome. (2021)
  • Author(s): Murase C, Takeichi T, Taki T, Yoshikawa T, Suzuki A, Ogi T, Suga Y, Akiyama M.
  • Journal Title: J Dermatol Sci Volume: 102 Issue: 2 Pages: 126-129
  • DOI: 10.1016/j.jdermsci.2021.03.003
  • NAID: 120007175359
  • Peer Reviewed
• [Journal Article] Acylceramide is a key player in skin barrier function: insight into the molecular mechanisms of skin barrier formation and ichthyosis pathogenesis. (2021)
  • Author(s): Akiyama M.
  • Journal Title: FEBS J Volume: 288 Issue: 7 Pages: 2119-2130
  • DOI: 10.1111/febs.15497
  • Peer Reviewed / Open Access
• [Journal Article] Recurrent KRT10 variant in ichthyosis with confetti. (2020)
  • Author(s): Takeichi T, Suga Y, Mizuno T, Okuno Y, Ichikawa D, Kono M, Lee JYW, McGrath JA, Akiyama M.
  • Journal Title: Acta Dermato-Venereol Volume: 100 Issue: 14 Pages: adv00209-adv00209
  • DOI: 10.2340/00015555-3570
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mild epidermolytic ichthyosis with palmoplantar keratoderma due to the KRT1 mutation p.lle479Thr. (2020)
  • Author(s): Murase Y, Tanahashi K, Takeichi T, Sugiura K, Aiyama A, Nishida K, Mitsuma T, Akiyama M.
  • Journal Title: J Dermatol Volume: 47 Issue: 9
  • DOI: 10.1111/1346-8138.15476
  • Peer Reviewed
• [Journal Article] 【難病研究の進歩】皮膚 先天性魚鱗癬. (2020)
  • Author(s): 秋山真志
  • Journal Title: 生体の科学 Volume: 71 Pages: 526-527
• [Journal Article] Hereditary Mucoepithelial Dysplasia and Autosomal-Dominant IFAP Syndrome Is a Clinical Spectrum Due to SREBF1 Variants (2020)
  • Author(s): Murase Chiaki、Takeichi Takuya、Nomura Toshifumi、Ogi Tomoo、Akiyama Masashi
  • Journal Title: Journal of Investigative Dermatology Volume: in press Issue: 6 Pages: 1596-1598
  • DOI: 10.1016/j.jid.2020.09.035
  • NAID: 120007175360
  • Peer Reviewed
• [Journal Article] Reduced stratum corneum acylceramides in autosomal recessive congenital ichthyosis with a NIPAL4 mutation. (2020)
  • Author(s): Murase Y, Takeichi T, Kawamoto A, Tanahashi K, Okuno Y, Takama H, Shimizu E, Ishikawa J, Ogi T, Akiyama M.
  • Journal Title: Journal of Dermatological Science Volume: 97 Issue: 1 Pages: 50-56
  • DOI: 10.1016/j.jdermsci.2019.12.001
  • NAID: 120006849002
  • Peer Reviewed / Open Access
• [Journal Article] SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation (2020)
  • Author(s): Takeichi T, Hirabayashi T, Miyasaka Y, Kawamoto A, Okuno Y, Taguchi S, Tanahashi K, Murase C, Takama H, Tanaka K, Boeglin WE, Calcutt MW, Watanabe D, Kono M, Muro Y, Ishikawa J, Ohno T, Brash AR, Akiyama M
  • Journal Title: J Clin Invest Volume: 130 Issue: 2 Pages: 890-903
  • DOI: 10.1172/jci130675
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deep phenotyping of ichthyosis follicularis with atrichia and photophobia syndrome associated with MBTPS2 mutations. (2020)
  • Author(s): Murase C, Takeichi T, Okuno Y, Ikumi K, Morita A, Akiyama M.
  • Journal Title: J Dermatol Volume: 47 Issue: 3
  • DOI: 10.1111/1346-8138.15210
  • Peer Reviewed
• [Journal Article] Aberrant CARD14 function might cause defective barrier formation. (2019)
  • Author(s): Murase Y, Takeichi T, Akiyama M.
  • Journal Title: J Allergy Clin Immunol. Volume: 143 Issue: 4 Pages: 1656-1657
  • DOI: 10.1016/j.jaci.2018.11.044
  • NAID: 120006652417
  • Peer Reviewed
• [Journal Article] Studies on differentiation-dependent expression and activity of distinct transglutaminases by specific substrate peptides using three dimensional reconstituted epidermis. (2019)
  • Author(s): Ｔａｎａｂｅ Ｙ．， Ｙａｍａｎｅ Ｍ， Ｋａｔｏ Ｍ．， Ｔｅｓｈｉｍａ Ｈ．， Ｋｕｒｉｂａｙａｓｈｉ Ｍ．， Ｔａｔｓｕｋａｗａ Ｈ．， Ｔａｋａｍａ Ｈ．， Ａｋｉｙａｍａ Ｍ．， Ｈｉｔｏｍｉ Ｋ．
  • Journal Title: FEBS J. Volume: in press Issue: 13 Pages: 2536-2548
  • DOI: 10.1111/febs.14832
  • Peer Reviewed
• [Journal Article] More than keratitis, ichthyosis, and deafness: multisystem effects of lethal GJB2 mutations. (2019)
  • Author(s): Lilly E, Bunick CG, Maley AM, Zhang S, Spraker MK, Theos AJ, Vivar KL, Seminario-Vidal L, Bennett AE, Sidbury R, Ogawa Y, Akiyama M, Binder B, Hadj-Rabia S, Morotti RA, Glusac EJ, Choate KA, Richard G, Milstone LM
  • Journal Title: J Am Acad Dermatol Volume: 80 Issue: 3 Pages: 617-625
  • DOI: 10.1016/j.jaad.2018.09.042
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome. (2018)
  • Author(s): Taki T, Takeichi T, Sugiura K, Akiyama M.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 12824-12824
  • DOI: 10.1038/s41598-018-30757-3
  • Peer Reviewed / Open Access
• [Journal Article] Cross-sectional survey on disease severity in Japanese patients with harlequin ichthyosis/ichthyosis: Syndromic forms and quality-of-life analysis in a subgroup. (2018)
  • Author(s): Murase C, Takeichi T, Shibata A, Nakatochi M, Kinoshita F, Kubo A, Nakajima K, Ishii N, Amano H, Masuda K, Kawakami H, Kanekura T, Washio K, Asano M, Teramura K, Akasaka E, Tohyama M, Hatano Y, Ochiai T, Moriwaki S, Sato T, Ishida-Yamamoto A, Seishima M, Kurosawa M, Ikeda S, Akiyama M.
  • Journal Title: J Dermatol Sci. Volume: 92 Issue: 2 Pages: 127-133
  • DOI: 10.1016/j.jdermsci.2018.08.008
  • NAID: 120006623824
  • Peer Reviewed
• [Journal Article] Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency. (2018)
  • Author(s): Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency.
  • Journal Title: Journal of lipid research Volume: 59 Issue: 12 Pages: 2413-1420
  • DOI: 10.1194/jlr.p087536
  • Peer Reviewed
• [Journal Article] Sterol profiles are valuable biomarkers for phenotype expression of Conradi-Hünermann-Happle syndrome with EBP mutations. (2018)
  • Author(s): Takeichi T, Honda A, Okuno Y, Kojima D, Kono M, Nakamura Y, Tohyama M, Tanaka T, Aoyama Y, Akiyama M.
  • Journal Title: Br J Dermatol. Volume: 179 Issue: 5 Pages: 1186-1188
  • DOI: 10.1111/bjd.16823
  • Peer Reviewed
• [Presentation] Dupilumabが奏効したNetherton症候群の一例. (2021)
  • Author(s): 秋山真志、村瀬千晶、滝 奉樹、武市拓也、須賀 康.
  • Organizer: 第295回日本皮膚科学会東海地方会
• [Presentation] 角化症を科学する (2020)
  • Author(s): 秋山真志
  • Organizer: 第71回日本皮膚科学会中部支部学術大会
  • Invited
• [Presentation] 遺伝性角化症かも？と思ったら (2019)
  • Author(s): 秋山真志
  • Organizer: 第35回日本臨床皮膚科医会総会・学術大会
  • Invited
• [Presentation] 表皮脂質の機能障害による疾患群：魚鱗癬と魚鱗癬症候群. (2019)
  • Author(s): 秋山真志
  • Organizer: 第61回日本脂質生化学会
  • Invited
• [Presentation] 表皮脂質が担う皮膚バリア機能 (2018)
  • Author(s): 秋山真志
  • Organizer: 第82回日本皮膚科学会東京支部学術大会（教育講演）（国内学会）
  • Invited
• [Presentation] 魚鱗癬・魚鱗癬症候群の病態から解き明かされる、表皮バリアの形成機構 (2018)
  • Author(s): 秋山真志
  • Organizer: 第91回日本生化学会大会（シンポジウム）（国内学会）
  • Invited
• [Remarks] 名古屋大学大学院医学系研究科皮膚科学分野のホームページ
  • URL: https://www.med.nagoya-u.ac.jp/derma/