A chemical genetic approach to exploring novel therapeutics targeting the integrated stress response

• Project/Area Number: 19H02853
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: The University of Tokushima
• Principal Investigator: OYADOMARI Seiichi 徳島大学, 先端酵素学研究所, 教授 (90502534)
• Co-Investigator(Kenkyū-buntansha): 親泊 美帆 徳島大学, 先端酵素学研究所, 特任助教 (00596158)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2021: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2020: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
• Keywords: 小胞体ストレス応答 / ケミカルバイオロジー / CRISPR / ゲノムワイドスクリーニング / CRISPRゲノムワイドスクリーニング

Outline of Research at the Start

本研究では、これまでの研究成果に基づき、ケミカルバイオロジーとCRISPRゲノムワイドスクリーニングを組み合わせて、化合物を手掛かりに統合的ストレス応答の全容解明と新たな治療法の開発に挑む。
研究期間内において、(1)統合的ストレス応答を制御する化合物や遺伝子の同定から新規制御機構の発見、(2) 同定した化合物と標的タンパク質の結合実証による新規制御機構の検証、(3) 同定した化合物による統合的ストレス応答異常モデルの治療効果の実証の３つの目標の達成を目指す。

Outline of Final Research Achievements

The integrated stress response (ISR) is triggered by various stress conditions such as endoplasmic reticulum (ER) stress, amino acid starvation, viral infection, and heme deficiency, and dysregulation of the ISR is implicated in the pathophysiology of various such as diabetes, neurodegenerative diseases, viral infection, and cancer. In this study, we have identified compounds that alleviate ER stress and ameliorate proteotoxicity in the cellular models of prion diseases (eLife 8, pii: e43302, 2019) and diabetes (Cell Chem Biol. S2451-9456(22)00002-2. 2022) through screening compound libraries. We have also found a novel regulatory mechanism by which activation of the ISR modulates appetite, and we have successfully demonstrated proof of the mechanism by taking advantage of genome editing techniques (iScience 24, 103448, 2021).

Academic Significance and Societal Importance of the Research Achievements

生物はすべからく外界の変化に適応して生き延びるために、ストレス応答を進化させてきた。ストレス応答は生存に必須であり、その破綻や暴走は疾患発症や死に直結する。疾患を克服し、健康寿命を延伸させるには、ストレス抵抗性を獲得する必要があり、そのためにはストレス応答の解明が必須である。本研究では、化合物ライブラリーから探索したヒット化合物を手がかりに、疾患発症に関連する新規のストレス応答機構を発見することができ、また疾患モデル細胞におけるヒット化合物による病態改善効果も実証することができ、学術的にも社会的にも意義のある研究成果が得られた。

Research Products

• [Journal Article] Identification of an endoplasmic reticulum proteostasis modulator that enhances insulin production in pancreatic β cells (2022)
  • Author(s): Miyake Masato、Sobajima Mitsuaki、Kurahashi Kiyoe、Shigenaga Akira、Denda Masaya、Otaka Akira、Saio Tomohide、Sakane Naoki、Kosako Hidetaka、Oyadomari Seiichi
  • Journal Title: Cell Chemical Biology Volume: 7 Issue: 6 Pages: 996-1009
  • DOI: 10.1016/j.chembiol.2022.01.002
  • Peer Reviewed
• [Journal Article] Integrated stress response regulates GDF15 secretion from adipocytes, preferentially suppresses appetite for a high-fat diet and improves obesity (2021)
  • Author(s): Miyake Masato、Zhang Jun、Yasue Akihiro、Hisanaga Satoshi、Tsugawa Kazue、Sakaue Hiroshi、Oyadomari Miho、Kiyonari Hiroshi、Oyadomari Seiichi
  • Journal Title: iScience Volume: 24 Issue: 12 Pages: 103448-103448
  • DOI: 10.1016/j.isci.2021.103448
  • Peer Reviewed / Open Access
• [Journal Article] Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway (2021)
  • Author(s): Li Jinghe、Inoue Ryota、Togashi Yu、Okuyama Tomoko、Satoh Aoi、Kyohara Mayu、Nishiyama Kuniyuki、Tsuno Takahiro、Miyashita Daisuke、Kin Tatsuya、Shapiro A.M. James、Chew Resilind Su Ern、Teo Adrian Kee Keong、Oyadomari Seiichi、Terauchi Yasuo、Shirakawa Jun
  • Journal Title: Diabetes Volume: 71 Issue: 3 Pages: 424-439
  • DOI: 10.2337/db21-0123
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ATF4-mediated transcriptional regulation protects against β-cell loss during endoplasmic reticulum stress in a mouse model (2021)
  • Author(s): Kitakaze Keisuke、Oyadomari Miho、Zhang Jun、Hamada Yoshimasa、Takenouchi Yasuhiro、Tsuboi Kazuhito、Inagaki Mai、Tachikawa Masanori、Fujitani Yoshio、Okamoto Yasuo、Oyadomari Seiichi
  • Journal Title: Molecular Metabolism Volume: 54 Pages: 101338-101338
  • DOI: 10.1016/j.molmet.2021.101338
  • Peer Reviewed / Open Access
• [Journal Article] Fgf10-CRISPR mosaic mutants demonstrate the gene dose-related loss of the accessory lobe and decrease in the number of alveolar type 2 epithelial cells in mouse lung (2020)
  • Author(s): Habuta, M., Yasue, A., Suzuki, K. I. T., Fujita, H., Sato, K., Kono, H., Takayama, A., Bando, T., Miyaishi, S., Oyadomari, S., Tanaka, E. & Ohuchi, H.
  • Journal Title: PloS one Volume: 15 Issue: 10 Pages: e0240333-e0240333
  • DOI: 10.1371/journal.pone.0240333
  • NAID: 120006959727
  • Peer Reviewed / Open Access
• [Journal Article] Activation of PERK-ATF4-CHOP pathway as a novel therapeutic approach for efficient elimination of HTLV-1-infected cells (2020)
  • Author(s): Ikebe E, Matsuoka S, Tezuka K, Kuramitsu M, Okuma K, Nakashima M,, Seiichiro Kobayashi S, Makiyama J, Yamagishi M, Oyadomari S, Uchimaru K, Hamaguchi I
  • Journal Title: Blood adv Volume: 4 Issue: 9 Pages: 1845-1858
  • DOI: 10.1182/bloodadvances.2019001139
  • Peer Reviewed / Open Access
• [Journal Article] The C-terminal region including the MH6 domain of Msx1 regulates skeletal development. (2020)
  • Author(s): Ichihara A, Yasue A, Mitsui SN, Arai D, Minegishi Y, Oyadomari S, Imoto I, Tanaka E.
  • Journal Title: Biochem Biophys Res Commun Volume: 526 Issue: 1 Pages: 62-69
  • DOI: 10.1016/j.bbrc.2020.03.068
  • NAID: 120006881395
  • Peer Reviewed / Open Access
• [Journal Article] Nanosecond pulsed electric fields induce the integrated stress response via reactive oxygen species-mediated heme-regulated inhibitor (HRI) activation (2020)
  • Author(s): Hamada Yoshimasa、Furumoto Yuji、Izutani Akira、Taniuchi Shusuke、Miyake Masato、Oyadomari Miho、Teranishi Kenji、Shimomura Naoyuki、Oyadomari Seiichi
  • Journal Title: PLOS ONE Volume: 15 Issue: 3 Pages: e0229948-e0229948
  • DOI: 10.1371/journal.pone.0229948
  • NAID: 120006869528
  • Peer Reviewed / Open Access
• [Journal Article] ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue. (2020)
  • Author(s): Kato H, Okabe K, Miyake M, Hattori K, Fukaya T, Tanimoto K, Beini S, Mizuguchi M, Torii S, Arakawa S, Ono M, Saito Y, Sugiyama T, Funatsu T, Sato K, Shimizu S, Oyadomari S, Ichijo H, Kadowaki H, Nishitoh H.
  • Journal Title: Life science alliance Volume: 3 Issue: 3 Pages: 201900576-201900576
  • DOI: 10.26508/lsa.201900576
  • NAID: 120006980545
  • Peer Reviewed / Open Access
• [Journal Article] Atovaquone is active against AML by upregulating the integrated stress pathway and suppressing oxidative phosphorylation (2019)
  • Author(s): Stevens AM, Xiang M, Heppler LN, Toxic I, Jiang K, Munoz JO, Gaikwad AS, Horton TM, Long X, Narayanan P, Seashore EL, Terrell MC, Rashid R, Krueger MJ, Mangubat-Medina AE, Ball ZT, Sumazin P, Walker SR, Hamada Y, Oyadomari S, Redell MS, Frank DA.
  • Journal Title: Blood Advances Volume: 3 Issue: 24 Pages: 4215-4227
  • DOI: 10.1182/bloodadvances.2019000499
  • Peer Reviewed
• [Journal Article] Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity (2019)
  • Author(s): Kitakaze Keisuke、Taniuchi Shusuke、Kawano Eri、Hamada Yoshimasa、Miyake Masato、Oyadomari Miho、Kojima Hirotatsu、Kosako Hidetaka、Kuribara Tomoko、Yoshida Suguru、Hosoya Takamitsu、Oyadomari Seiichi
  • Journal Title: eLife Volume: 8
  • DOI: 10.7554/elife.43302
  • NAID: 120006941114
  • Peer Reviewed / Open Access