Study on endoplasmic reticulum-associated degradation (ERAD) dysfunction causing lethal effects in hypoxia
| Project/Area Number |
17K07358
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Functional biochemistry
|
|---|
| Research Institution | National Cardiovascular Center Research Institute |
|---|
Principal Investigator |
Koichi Kokame 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (40270730)
|
|---|
| Project Period (FY) |
2017-04-01 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
|
|---|
| Keywords | 細胞内タンパク質分解 / 小胞体関連分解 / 小胞体ストレス / タンパク質品質管理 / 低酸素ストレス / 低酸素 |
|---|
| Outline of Final Research Achievements |
The cellular mechanism to remove abnormal proteins accumulated in the endoplasmic reticulum (ER) is called ER-associated protein degradation (ERAD). In this study, we analyzed mice deficient in the Herp and Derlin-3 proteins that work in ERAD. These mice were vulnerable to chronic hypoxia, and the possible cause was cardiac or systemic maladaptation to hypoxic stress. As a result of the cardiac function evaluation, it was found that the left ventricular ejection fraction was decreased in these mice. Furthermore, by biochemical analysis using pancreas in which Derlin-3 is constitutively expressed and liver in which Derlin-3 expression is strongly induced by ER stress, the composition of the ERAD complex changes in response to the stress. Derlin-3 seemed to have a switch-molecule role.
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究では、HerpおよびDerlin-3欠損マウスの解析からERADの生理的な重要性を明らかにし、その基盤となる分子機構を解明することを目的とした。いずれのマウスも、低酸素負荷時だけでなく通常飼育条件下においても心機能低下を示したことから、ERADは発生段階あるいは出生直後における正常な心機能獲得に必須であることが示唆された。Derlin-3欠損マウスでは脂質代謝異常が起こる可能性も見出され、機序解明を進めている。ERAD複合体の構成が小胞体ストレスで変化することも本研究による新たな発見であり、原著論文として投稿した。ERAD機能と生活習慣病との関連を研究する基盤になると期待される。
|
Report
(4 results)
Research Products
(51 results)
-
-
-
-
-
-
-
-
-
-
-
-
[Journal Article] The international hereditary thrombotic thrombocytopenic purpura (TTP) registry: Key findings at enrolment until 20172019
Author(s)
van Dorland HA, Mansouri Taleghani M, Sakai K, Friedman KD, George JN, Hrachovinova I, Knobl PN, von Krogh AS, Schneppenheim R, Aebi-Huber I, Butikofer L, Largiader CR, Cermakova Z, Kokame K, Miyata T, Yagi H, Terrell DR, Vesely SK, Matsumoto M, Lammle B, Fujimura Y, Kremer Hovinga JA
-
Journal Title
Haematologica
Volume: 印刷中
Issue: 10
Pages: 2107-2115
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
[Journal Article] Effects of low-dose combined oral contraceptives and protein S K196E mutation on anticoagulation factors: a prospective observational study2019
Author(s)
Takekazu Miyoshi, Hisato Oku, Saiko Asahara, Akira Okamoto, Koichi Kokame, Michikazu Nakai, Kunihiro Nishimura, Fumiyuki Otsuka, Aya Higashiyama, Jun Yoshimatsu, Toshiyuki Miyata
-
Journal Title
International Journal of Hematology
Volume: 印刷中
Issue: 6
Pages: 641-649
DOI
Related Report
Peer Reviewed
-
-
-
-
-
-
-
-
[Journal Article] For TTP group of Blood Coagulation Abnormalities Research Team, Research on Rare and Intractable Disease supported by Health, Labour, and Welfare Sciences Research Grants.: Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) 2017 in Japan.2017
Author(s)
Matsumoto M, Fujimura Y, Wada H, Kokame K, Miyakawa Y, Ueda Y, Higasa S, Moriki T, Yagi H, Miyata T, Murata M;
-
Journal Title
Int J Hematol
Volume: 106
Issue: 1
Pages: 3-15
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
[Presentation] Complete failure of integrin αIIbβ3 activation in kinetic assay associates with severe bleeding problems in a patient with kindlin-3 deficiency2017
Author(s)
H Kato, Y Ito, H Kashiwagi, Y Morikawa, K Akuta, N Nishiura, S Honda, K Kokame, T Miyata, Y Kanakura, Y Tomiyama
Organizer
The 26th Congress of the International Society on Thrombosis and Haemostasis
Related Report
Int'l Joint Research
-
-
-
-
-
-
-
-
-
