Necroptosis-tartgeted therapy for heart failure
Project/Area Number |
19K08544
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 53020:Cardiology-related
|
Research Institution | Sapporo Medical University |
Principal Investigator |
|
Co-Investigator(Kenkyū-buntansha) |
丹野 雅也 札幌医科大学, 医学部, 准教授 (00398322)
久野 篤史 札幌医科大学, 医学部, 准教授 (30468079)
|
Project Period (FY) |
2019-04-01 – 2022-03-31
|
Project Status |
Completed (Fiscal Year 2021)
|
Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
|
Keywords | 心不全 / 細胞死 / ネクロプトーシス / 拡張型心筋症 / ネクローシス / 心筋細胞 / mTOR |
Outline of Research at the Start |
申請者らは、細胞増殖及び成長のmaster regulatorとして知られている哺乳類ラパマイシン標的蛋白質複合体1 (mTORC1) の恒常的活性化が心不全発症及び増悪に関係していることを報告した。さらに、mTORC1の恒常的活性化がプログラム細胞死の一つであるネクロプトーシスを誘導することを解明した。 本研究では、“mTORC1恒常的活性化とネクロプトーシスの分子機構連関”及び“心不全の病態形成におけるネクロプトーシスの役割”を明らかにする。
|
Outline of Final Research Achievements |
We found increased cardiomyocyte expression of nuclear p-MLKL, an executor of necroptosis, in patients with nonischemic dilated cardiomyopathy (NICM), but its clinical significance remains unclear. Endomyocardial biopsy specimens were obtained from 57 patients with NICM (56±15 years old, 68% male). Nuclear p-MLKL levels were determined by immunostaining against phospho-Ser358-MLKL. Using median nuclear p-MLKL expression levels, patients were classified into a high nuclear p-MLKL group and a low nuclear p-MLKL group. Adverse event was defined as composite of death or admission for heart failure or ventricular arrhythmia. Results of Kaplan-Meier survival curve analyses showed that the adverse event-free survival rate was lower in the high nuclear p-MLKL group than in the low nuclear p-MLKL group (4% vs. 31%, p=0.021). Enhanced expression of nuclear p-MLKL in cardiomyocytes predicts future adverse events, suggesting possible involvement of necroptosis in progression of NICM.
|
Academic Significance and Societal Importance of the Research Achievements |
癌治療においては発現している分子や遺伝子をガイドに分子標的治療が行われ、一定の成果をあげている。心不全においても動物実験レベルでは様々な分子標的が想定されているが臨床応用されておらず、症状や心不全進行の程度に応じた薬物治療が今なお主体となっている。本研究は申請者による“心不全のテーラーメイド治療プロジェクト”の一環であり、心筋生検組織からリン酸化MLKL亢進群を抽出し、分子標的治療を行うことが最終目標である。心不全に対する分子標的治療の最初の一歩となり、今後の波及効果にも期待を持てるプロジェクトになると考えている。
|
Report
(4 results)
Research Products
(46 results)
-
-
-
-
-
-
-
-
-
-
-
-
-
[Journal Article] Clinical Risk Factors and Prognostic Impact of Osteoporosis in Patients With Chronic Heart Failure2020
Author(s)
Katano S, Yano T, Tsukada T, Kouzu H, Honma S, Inoue T, Takamura Y, Nagaoka R, Ishigo T, Watanabe A, Ohori K, Koyama M, Nagano N, Fujito T, Nishikawa R, Takashima H, Hashimoto A, Katayose M, Miura T.
-
Journal Title
Circulation Journal
Volume: 84
Issue: 12
Pages: 2224-2234
DOI
NAID
ISSN
1346-9843, 1347-4820
Year and Date
2020-11-25
Related Report
Peer Reviewed / Open Access
-
-
-
[Journal Article] Empagliflozin attenuates acute kidney injury after myocardial infarction in diabetic rats2020
Author(s)
Kuno A, Kimura Y, Mizuno M, Oshima H, Sato T, Moniwa N, Tanaka M, Yano T, Tanno M, Miki T, Miura T.
-
Journal Title
Sci Rep
Volume: 29
Issue: 1
Pages: 7238-7238
DOI
Related Report
Peer Reviewed / Open Access
-
[Journal Article] Hemodynamic Collapse After Influenza Vaccination: A Vaccine-Induced Fulminant Myocarditis?2020
Author(s)
Nagano N, Yano T, Fujita Y, Koyama M, Hasegawa R, Nakata J, Nishikawa R, Murakami N, Fujito T, Mochizuki A, Kouzu H, Muranaka A, Kokubu N, Miura T.
-
Journal Title
Can J Cardiol
Volume: 36
Issue: 9
Pages: 1554.e5-1554.e7
DOI
Related Report
Peer Reviewed
-
[Journal Article] Distinct intra-mitochondrial localizations of pro-survival kinases and regulation of their functions by DUSP5 and PHLPP-12020
Author(s)
Ohwada W, Tanno M, Yano T, Ong SB, Abe K, Sato T, Kuno A, Miki T, Sugawara H, Igaki Y, Miura T.
-
Journal Title
Biochim Biophys Acta Mol Basis Dis
Volume: 1866
Issue: 10
Pages: 165851-165851
DOI
Related Report
Peer Reviewed / Open Access
-
[Journal Article] Overestimation of glomerular filtration rate by creatinine-based equation in heart failure patients is predicted by a novel scoring system2020
Author(s)
Ishigo T, Katano S, Yano T, Kouzu H, Ohori K, Nakata H, Nonoyama M, Inoue T, Takamura Y, Nagaoka R, Kondo F, Nakano K, Takada R, Kitagawa M, Kimyo T, Miura T.
-
Journal Title
Geriatr Gerontol Int
Volume: 20
Issue: 8
Pages: 752-758
DOI
Related Report
Peer Reviewed
-
[Journal Article] Cardiac Light Chain Deposition Disease Mimicking Immunoglobulin Light Chain Amyloidosis: Two Branches of the Same Tree2020
Author(s)
Osanami A, Yano T, Takemura G, Ikeda H, Inyaku M, Toda Y, Kamiyama N, Sugawara H, Gocho Y, Fujito T, Nagano N, Takahashi S, Muranaka A, Tanaka M, Moniwa N, Murase K, Takada K, Kuroda H, Ogawa Y, Miura T
-
Journal Title
Circ Cardiovasc Imaging
Volume: 13
Issue: 9
DOI
Related Report
Peer Reviewed
-
-
[Journal Article] Independent link between peripheral artery disease and muscle wasting in patients with heart failure2020
Author(s)
Ohori K, Yano T, Katano S, Kouzu H, Inoue T, Takamura Y, Nagaoka R, Ishigo T, Koyama M, Nagano N, Fujito T, Nishikawa R, Miura T.
-
Journal Title
ESC Heart Fail (supported by 19K08544)
Volume: 7
Issue: 5
Pages: 3252-3256
DOI
Related Report
Peer Reviewed / Open Access
-
[Journal Article] Assessment of prognosis in immunoglobulin light chain amyloidosis patients with severe heart failure: a predictive value of right ventricular function.2020
Author(s)
Nagano N, Yano T, Fujita Y, Kouzu H, Koyama M, Ikeda H, Yasui K, Muranaka A, Nishikawa R, Takahashi R, Kishiue N, Yuda S, Miura T.
-
Journal Title
Heart Vessels
Volume: 35
Issue: 4
Pages: 521-521
DOI
Related Report
Peer Reviewed
-
[Journal Article] Vanishing Cardiac Tumor: Cardiac Involvement in Methotrexate-Associated Lymphoproliferative Disorders.2019
Author(s)
Kishiue N, Yano T, Koyama M, Nishikawa R, Nagano N, Kouzu H, Kokubu N, Kawamura R, Muranaka A, Kikuchi S, Tsuchida A, Miura T.
-
Journal Title
Circ Cardiovasc Imaging
Volume: 12
Issue: 11
DOI
Related Report
Peer Reviewed
-
[Journal Article] mTORC1 Inhibition Attenuates Necroptosis Through RIP1 Inhibition-Mediated TFEB Activation2019
Author(s)
Abe K, Yano T, Tanno M, Miki T, Kuno A, Sato T, Kouzu H, Nakata K, Ohwada W, Kimura Y, Sugawara H, Shibata S, Igaki Y, Ino S, Miura T.
-
Journal Title
Biochim Biophys Acta Mol Basis Dis .
Volume: 1865
Issue: 12
Pages: 165552-165552
DOI
Related Report
Peer Reviewed
-
[Journal Article] Utility and safety of tocilizumab in Takayasu arteritis with severe heart failure and muscle wasting.2019
Author(s)
Yano T, Osanami A, Shimizu M, Katano S, Nagano N, Kouzu H, Koyama M, Muranaka A, Harada R, Doi H, Kawaharada N, Miura T.
-
Journal Title
ESC Heart Fail
Volume: 6
Issue: 4
Pages: 894-894
DOI
Related Report
Peer Reviewed / Open Access
-
-
-
-
[Presentation] Barthel Index score predicts mortality in elderly heart failure: a goal of comprehensive cardiac rehabilitation2021
Author(s)
Katano S, Yano T, Ohori K, Kouzu H, Nagaoka R, Honma S, Shimomura K, Numazawa R, Koyama M, Nagano N, Fujito T, Nishikawa R, Hashimoto A, Katayose M, Miura T.
Organizer
ESC congress
Related Report
Int'l Joint Research
-
[Presentation] Clinical determinants and prognostic impact of osteoporosis in patients with chronic heart failure2020
Author(s)
Katano S., Yano T., Tsukada T., Kouzu H., Honma S., Inoue T., Takamura Y., Nagaoka R., Ohori K., Koyama M., Nagano N., Nishikawa R., Hashimoto A., Katayose M., Miura T.
Organizer
ESC congress 2020
Related Report
Int'l Joint Research
-
-
[Presentation] Phosphorylated MLKL, an Executor of Necroptosis, Localized in the Nucleus and Intercalated Disc Plays Distinct Roles in Nonischemic Dilated Cardiomyopathy.2020
Author(s)
Fujita Y, Yano T, Nagano N, Nishikawa R, Kamiyama N, Fujito T, Mochizuki A, Koyama M, Kouzu H, Muranaka A, Nagahara D, Tannno M, Miki T, Miura T.
Organizer
日本循環器学会年次学術集会
Related Report
-
-
-
-
[Presentation] Activation of necroptotic pasthway by downregulated caspase-8 expression is associated with progression of left ventricular remodeling in nonischemic dilated cardiomyopathy.2019
Author(s)
Fujita Y, Yano T, Abe K, Nagano N, Kamiyama N, Fujito T, Mochizuki A, Koyama M, Kouzu H, Muranaka A, Nagahara D, Tanno M, Miki T, Miura T.
Organizer
ESC congress 2019
Related Report
Int'l Joint Research
-
-
[Presentation] Low energy intake predicts readmission of elderly heart failure patients independently of nutritional status.2019
Author(s)
Shimomura K, Katano S, Yano T, Ohori K, Honma S, Watanabe A, Ishigo T, Fujito T, Nagano N, Koyama M, Kouzu H, Hashimoto A, Miura T.
Organizer
ESC congress 2019
Related Report
Int'l Joint Research
-
[Presentation] Impact of body composition analysis on prediction of short-term readmission events in heart failure: muscle wasting vs. obesity.2019
Author(s)
Ohori K, Yano T, Katano S, Honma S, Shimomura K, Watanabe A, Ishigo T, Fuito T, Nagano N, Koyama M, Kouzu H, Hashimoto A, Miura T.
Organizer
ESC congress 2019
Related Report
Int'l Joint Research
-
[Presentation] Reduced level of caspase-8, an endogenous inhibitor of necroptosis, is associated with left ventricular enlargement in dilated cardiomyopathy.2019
Author(s)
Fujita Y, Yano T, Nagano N, Kamiyama N, Fujito T, Mochizuki A, Koyama M, Kouzu H, Muranaka A, Nagahara D, Tanno M, Miki T, Miura T.
Organizer
第83 回日本循環器学会年次学術集会
Related Report
-
-
-
-
[Presentation] Distinct expressions of caspase-8 and phospho-MLKL, necroptosis regulatory proteins, in nonischemic dilated cardiomyopathy.2019
Author(s)
Fujita Y, Yano T, Abe K, Nagano N, Nishikawa R, Kamiyama N, Fujito T, Mochizuki A, Koyama M, Kouzu H, Muranaka A, Nagahara D, Tanno M, Miki T, Miura T.
Organizer
第23 回 日本心不全学会学術集会
Related Report
-