Development of a novel therapy for lifestyle-related diseases and chronic organ damage by targeting the homeostatic regulation within the body

• Project/Area Number: 18H02602
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Shinshu University
• Principal Investigator: Shindo Takayuki 信州大学, 学術研究院医学系, 教授 (90345215)
• Co-Investigator(Kenkyū-buntansha): 神吉 昭子 信州大学, 学術研究院医学系, 助教 (10397309) ; 村田 敏規 信州大学, 学術研究院医学系, 教授 (50253406) ; 桜井 敬之 信州大学, 学術研究院医学系, 准教授 (80317825)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 分子血管病学 / 生理活性因子 / 癌転移 / 癌関連線維芽細胞 / 生活習慣病 / 臓器障害 / 臓器不全

Outline of Final Research Achievements

In this study, we focused on RAMP, a receptor activity-modifying protein that regulates the function of the calcitonin superfamily (adrenomedullin, CGRP, and so on) known to have various bioactivities, as a new target for drug discovery.
Although RAMP has multiple sub-isoforms, we have found that each RAMP cleverly processes and translates the information of bioactive factors provided as input, resulting in a diversity of physiological functions as output. We focused on the functional differentiation of RAMP2 and RAMP3 and elucidated the relationship between their abnormalities and pathological conditions. These results are expected to lead to new drug discovery for lifestyle-related diseases and chronic organ disorders.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会に突入した我が国においては、生活習慣病や慢性臓器障害への医学的対策が喫緊の課題である。RAMPが生活習慣病や慢性臓器障害の治療標的として応用展開できれば、これらの問題の解決につながり、医学と医療に大きな貢献ができると期待される。また生活習慣病に対する治療薬の開発は、医療の在り方をより予防の方にシフトさせることにつながり、国民の福祉に寄与しつつ医療費を抑制することにつながる。

Research Products

• [Journal Article] Adrenomedullin-RAMP2 system ameliorates pulmonary fibrosis by regulating TGF-β-Smads pathway and differentiation of myofibroblasts. (2021)
  • Author(s): Wei Y, Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui1 N, Kakihara S, Zhao Y, Aruga K, Sanjo H, Shindo T.
  • Journal Title: Endocrinology. Volume: in press
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress. (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Tanaka M, Wei Y, Kakihara S, Zhao Y, Aruga K, Kawagishi H, Nakada T, Yamada M, ShindoT
  • Journal Title: Endocrinology. Volume: in press
  • Peer Reviewed
• [Journal Article] Adrenomedullin-receptor activity-modifying protein 2 system ameliorates subretinal fibrosis by suppressing epithelial-mesenchymal transition in age-related macular degeneration (2021)
  • Author(s): Tanaka M, Kakihara S, Hirabayashi K, Imai A, Toriyama Y, Iesato Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Cui N, Wei Y, Zhao Y, Aruga K, Yamauchi A, Murata T, Shindo T
  • Journal Title: Am J Pathol Volume: 191(4) Issue: 4 Pages: 652-668
  • DOI: 10.1016/j.ajpath.2020.12.012
  • Peer Reviewed
• [Journal Article] Mid-regional pro-adrenomedullin is a novel biomarker for arterial stiffness as the criterion for vascular failure in a cross-sectional study (2021)
  • Author(s): Koyama T, Kuriyama N, Suzuki Y, Saito S, Tanaka R, Iwao M, Tanaka M, Maki T, Itoh H, Ihara M, Shindo T, Uehara R.
  • Journal Title: Sci Rep. Volume: 11 Issue: 1 Pages: 305-305
  • DOI: 10.1038/s41598-020-79525-2
  • Peer Reviewed / Open Access
• [Journal Article] Placental extract ameliorates liver fibrosis in a methionine- and choline-deficient diet-induced mouse model of non-alcoholic steatohepatitis (2020)
  • Author(s): Yamauchi A. Tone T, Tokedo A, Igarashi K, Sugimoto K, Miyai H, Deng D, Nakamura J, Lim HS, Kaku T, Hirano E, Shindo T.
  • Journal Title: Biomedical Research Volume: 41 Issue: 1 Pages: 1-12
  • DOI: 10.2220/biomedres.41.1
  • NAID: 130007801485
  • ISSN: 0388-6107, 1880-313X
  • Year and Date: 2020-02-01
  • Peer Reviewed
• [Journal Article] Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts (2020)
  • Author(s): Dai K, Tanaka M, Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Kawate H, Cui N, Wei Y, Tanaka M, Kakihara S, Matsui S, Shindo T
  • Journal Title: Oncogene Volume: 39(9) Issue: 9 Pages: 1914-1930
  • DOI: 10.1038/s41388-019-1112-z
  • Peer Reviewed
• [Journal Article] Investigation of the therapeutic mechanism of subthreshold micropulse laser irradiation in retina (2020)
  • Author(s): Kazutaka Hirabayashi, Shinji Kakihara, Masaaki Tanaka, Takayuki Shindo, Toshinori Murata
  • Journal Title: Graefe's Archive for Clinical and Experimental Ophthalmology Volume: 258 Issue: 5 Pages: 1039-1047
  • DOI: 10.1007/s00417-020-04638-3
  • Peer Reviewed
• [Journal Article] Placental extract suppresses cardiac hypertrophy and fibrosis in an angiotensin II-induced cachexia model in mice (2019)
  • Author(s): Yamauchi Akihiro、Kamiyoshi Akiko、Sakurai Takayuki、Miyazaki Hiroyuki、Hirano Eiichi、Lim Hong Seok、Kaku Taiichi、Shindo Takayuki
  • Journal Title: Heliyon Volume: 5 Issue: 10 Pages: e02655-e02655
  • DOI: 10.1016/j.heliyon.2019.e02655
  • Peer Reviewed / Open Access
• [Journal Article] Porcine placental extract facilitates memory and learning in aged mice (2019)
  • Author(s): Yamauchi Akihiro、Tone Takahiro、Sugimoto Koji、Seok Lim Hong、Kaku Taiichi、Tohda Chihiro、Shindo Takayuki、Tamada Koji、Mizukami Yoichi、Hirano Eiichi
  • Journal Title: Food Science & Nutrition Volume: 7 Issue: 9 Pages: 2995-3005
  • DOI: 10.1002/fsn3.1156
  • Peer Reviewed / Open Access
• [Journal Article] Endogenous Calcitonin Gene-Related Peptide Deficiency Exacerbates Postoperative Lymphedema by Suppressing Lymphatic Capillary Formation and M2 Macrophage Accumulation (2019)
  • Author(s): Matsui S, Tanaka M, Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Kawate H, Dai K, Cui N, Wei Y, Tanaka M, Kakihara S, Nakamura K, Yamauchi A, Ishida K, Tanaka S, Kawamata M, Shindo T
  • Journal Title: Am J Pathol Volume: 189(12) Issue: 12 Pages: 2487-2502
  • DOI: 10.1016/j.ajpath.2019.08.011
  • Peer Reviewed
• [Journal Article] Development of a mouse iron overload-induced liver injury model and evaluation of the beneficial effects of placenta extract on iron metabolism (2019)
  • Author(s): Yamauchi A. Kamiyoshi A, Sakurai T, Miyazaki H, Hirano E, Lim HS, Kaku T, Shindo T.
  • Journal Title: Heliyon. Volume: 5 Issue: 5 Pages: e01637-e01637
  • DOI: 10.1016/j.heliyon.2019.e01637
  • Peer Reviewed / Open Access
• [Journal Article] Bindel-PCR: a novel and convenient method for identifying CRISPR/Cas9-induced biallelic mutants through modified PCR using Thermus aquaticus DNA polymerase (2019)
  • Author(s): Sakurai Takayuki、Kamiyoshi Akiko、Takei Norio、Watanabe Satoshi、Sato Masahiro、Shindo Takayuki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 9923-9923
  • DOI: 10.1038/s41598-019-46357-8
  • Peer Reviewed / Open Access
• [Journal Article] Development of a novel model of central retinal vascular occlusion and the therapeutic potential of the adrenomedullin-RAMP2 system. (2019)
  • Author(s): Hirabayashi K, Tanaka M, Imai A, Toriyama Y, Iesato Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Dai K, Cui N, Wei Y, Nakamura K, Iida S, Matsui S, Yamauchi A, Murata T, Shindo T.
  • Journal Title: Am J Pathol. Volume: 189 Issue: 2 Pages: 449-466
  • DOI: 10.1016/j.ajpath.2018.10.021
  • Peer Reviewed
• [Journal Article] Regulation of cardiovascular development and homeostasis by the adrenomedullin-RAMP system (2019)
  • Author(s): Shindo T, Tanaka M, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Yamauchi A, Sakurai T.
  • Journal Title: Peptides. Volume: 111 Pages: 55-61
  • DOI: 10.1016/j.peptides.2018.04.004
  • Peer Reviewed
• [Journal Article] Development of a novel model of central retinal vascular occlusion and the therapeutic potential of the adrenomedullin-RAMP2 system. (2019)
  • Author(s): Hirabayashi K, Tanaka M, Imai A, Toriyama Y, Iesato Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Dai K, Cui N, Wei Y, Nakamura K, Iida S, Matsui S, Yamauchi A, Murata T, Shindo T.
  • Journal Title: Am J Pathol. Volume: 189 Pages: 449-466
  • DOI: 10.1016/j.peptides.2018.10.006
  • Peer Reviewed
• [Journal Article] Endogenous calcitonin gene-related peptide suppresses ischemic brain injuries and progression of cognitive decline (2018)
  • Author(s): Zhai L, Tanaka M, et al.
  • Journal Title: J Hypertens. Volume: 36 Issue: 4 Pages: 876-891
  • DOI: 10.1097/hjh.0000000000001649
  • Peer Reviewed / Open Access
• [Presentation] Adrenomedullin-RAMP2 system regulates vascular endothelial homeostasis, which suppresses hematogenous and lymphogenous metastasis. (2021)
  • Author(s): Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui N, Wei Y, Tanaka M, Kakihara S, Zhao Y, Kasahara T, Aruga K, Shindo T
  • Organizer: 第85回日本循環器学会
• [Presentation] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Wei Y, Tanaka M, Kakihara S, Zhao Y, Kasahara T, Aruga K, Shindo T
  • Organizer: 第85回日本循環器学会
• [Presentation] Adrenomedullin-RAMP2 system ameliorates age-related macular degeneration by suppressing choroidal neovascularization and subretinal fibrosis (2021)
  • Author(s): Tanaka M, Kakihara S, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Cui N, Wei Y, Zhao Y, Kasahara T, Aruga K, Shindo T
  • Organizer: 第85回日本循環器学会
• [Presentation] アドレノメデュリン-RAMP2システムの糖尿病合併症への応用 (2020)
  • Author(s): 新藤隆行
  • Organizer: 第49回日本心脈管作動物質学会
  • Invited
• [Presentation] Pathophysiological significance of adrenomedullin-RAMP2 system in age-related macular degeneration (2019)
  • Author(s): Tanaka M, Hirabayashi K, Iesato Y, Imai A, Toriyama Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Yamauchi A, Murata T, Shindo T.
  • Organizer: The Association for Research in Vision and Ophthalmology (ARVO) 2019
  • Int'l Joint Research
• [Presentation] シンポジウム がんと心脈管作動物質との新たな接点 アドレノメデュリン-RAMP2系による血管恒常性制御機構と、癌転移抑制法への展開 (2019)
  • Author(s): 新藤隆行
  • Organizer: 第48回日本心脈管作動物質学会
  • Invited
• [Presentation] シンポジウム 糖尿病における血管病態の共通項を巡って Vascular homeostasis regulated by adrenomedullin-RAMP2 system and its application for diabetic vascular complications (2018)
  • Author(s): 新藤隆行
  • Organizer: 第61回日本糖尿病学会
  • Invited
• [Book] Methods Mol Biol. (2019)
  • Author(s): Sakurai T, Kamiyoshi A, Ohtsuka M, Gurumurthy CB, Sato M, Shindo T.
  • Total Pages: 15
  • Publisher: Springer
• [Book] Results Probl Cell Differ (2018)
  • Author(s): Sakurai T, Shindo T, Sato M.
  • Total Pages: 16
  • Publisher: Springer
• [Remarks] 信州大学医学部 循環病態学教室
  • URL: http://www7a.biglobe.ne.jp/~shindo/