Circadian Rhythm as a Therapeutic Target for Perioperative Cardioprotection
昼夜节律作为围手术期心脏保护的治疗目标
基本信息
- 批准号:10659089
- 负责人:
- 金额:$ 66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-11 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAREG geneARNTL geneAddressAmino AcidsAmphiregulinAnticoagulationApplications GrantsAreaBindingBiochemicalBiopsyCardiac Surgery proceduresCircadian RhythmsClinicalCo-ImmunoprecipitationsComplexCritical CareCryoelectron MicroscopyDNADataExposure toGenesGenetic TranscriptionGenetic studyGoalsHemorrhageHeterodimerizationHourHypoxiaIn SituIn VitroInfarctionInjuryInterventionLeftLeft ventricular structureLinkMapsMass Spectrum AnalysisMediatingMedicineModelingMorbidity - disease rateMusMuscle CellsMyocardial IschemiaMyocardial ReperfusionMyocardial Reperfusion InjuryMyocardiumMyosin ATPaseOperative Surgical ProceduresOutcomePathway interactionsPatient-Focused OutcomesPatientsPatternPeriodicityPerioperativePharmacology StudyPlatelet InhibitorsPreventionProspective StudiesProteinsRegulationResearch ProposalsResistanceResolutionResponse ElementsRetrospective StudiesRiskRoleSeveritiesSignal TransductionSiteStructureTherapeutic InterventionTimeTransgenic MiceVariantVentricularaortic valve replacementbHLH-PAS factor HLFbiophysical analysiscardioprotectioncircadiandifferential expressionelectron densityin vivomortalitymouse modelmyocardial injurynovelnovel strategiesnovel therapeutic interventionorgan injurypercutaneous coronary interventionpharmacologicpreventpromoterprotective pathwayrandomized, clinical trialstargeted treatmenttherapeutic targettranscription factortranscriptome sequencingtreatment strategy
项目摘要
PROJECT SUMMARY
The main goal of this grant application is to target circadian rhythm for perioperative cardioprotection.
Perioperative myocardial ischemia-reperfusion injury (IRI) and infarction continue to be major causes of morbidity
and mortality in surgical patients. However, percutaneous coronary intervention in combination with
anticoagulation and platelet inhibitors may be unsuitable in the perioperative setting due to the risk of bleeding
from the surgical site. Finding novel pharmacologic or interventional strategies to render the myocardium more
resistant to the deleterious effects of myocardial IRI would be highly significant for perioperative and critical care
medicine. Previous studies indicate that the occurrence of myocardial IRI follows a circadian pattern which could
be linked to an interaction between circadian rhythm and hypoxia signaling. Thus, the current application is
focused on identifying circadian mechanisms that could be targeted therapeutically to dampen myocardial IRI.
To study the circadian control of myocardial IRI, we established a murine model of in situ myocardial IRI and
found the smallest infarct sizes at zeitgeber time (ZT) 8 (3 pm), and largest infarct sizes at ZT 20 (3 am).
Subsequent unbiased RNA sequencing of the area at risk from the left ventricle of mice exposed to myocardial
IRI at ZT8 versus ZT20 pointed us toward the core circadian transcription factor - Bmal1. Similarly, RNA-seq
data from left ventricular biopsies of patients undergoing cardiac surgery in the morning versus afternoon groups
confirmed BMAL1 as the most differentially expressed gene. In functional studies, using transgenic mice with
myocyte-specific deletion of Bmal1 (Bmal1loxp/loxp Myosin Cre+ mice), we observed complete blunting of the
cardioprotective effect at ZT8. Co-immunoprecipitation followed by mass spectrometry identified hypoxia-
inducible factor 2-alpha (HIF2A) as a binding partner for BMAL1. Similar to Bmal1loxp/loxp Myosin Cre+ mice, we
observed abolished cardioprotection at ZT8 in Hif2aloxp/loxp Myosin Cre+ mice. Subsequent biochemical and
biophysical studies revealed a direct interaction between BMAL1 and HIF2A showing a 4.5 Å electron density
map of the BMAL1/HIF2A heterodimer in complex with hypoxia-response element (HRE) DNA. Finally, we
identified amphiregulin (AREG) as a critical transcriptional co-target for BMAL1/HIF2A heterodimer in mediating
circadian-dependent cardioprotection. Thus, we hypothesize that BMAL1 and HIF2A form a transcriptionally
active complex critical in mediating circadian-dependent cardioprotection via daytime-dependent
regulation of AREG. We propose three Specific Aims to address this hypothesis: (1) Characterize the interaction
between BMAL1 and HIF2A and their functional roles during hypoxia in vitro or myocardial IRI in vivo. (2) Study
the co-target gene of BMAL1/HIF2A – AREG in mediating circadian-dependent cardioprotection. (3) Target
BMAL1/HIF2A for cardioprotection and proof-of-principle studies during perioperative myocardial IRI.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Holger K. Eltzschig其他文献
Hypoxanthine-guanine phosphoribosyltransferase deficiency
次黄嘌呤鸟嘌呤磷酸核糖转移酶缺乏症
- DOI:
10.1007/978-3-540-29676-8_917 - 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
D. Metze;V. F. Cury;Ricardo S. Gomez;L. Marco;Dror Robinson;Eitan Melamed;Alexander K. C. Leung;Jae;Yoichi Matsubara;Keiya Tada;S. Sancak;Ralf Paschke;S. Kupka;Stefan K. Plontke;H. Zenner;Gohar Azhar;Jeanne Y. Wei;Y. Kang;Katsuhiko Yoshizawa;Abraham Nyska;Graeme Jones;Kathy Triantafilou;P. Lepper;Johannes Bode;C. Kashtan;Klaus Schümann;Günter Weiss;C. Skerka;Christoph Licht;P. Zipfel;H. Cate;Mark Oette;D. Häussinger;Isabelle Ruel;P. Couture;Benoît Lamarche;S. Siegmund;Stephan L. Haas;Manfred V. Singer;Tobias Heintges;Ralf Kubitz;Andreas Erhardt;F. Lammert;J. Lorenzen;Hubert E. Blum;Darius Moradpour;Georg H. Merker;Matthias Wettstein;Mónica Guevara;Pere Ginés;H. Cate;Ulrich Heininger;Markus Pfister;M. Schmitt;A. Schinkel;D. Poldermans;Jeroen J. Bax;Heimo Mairbäurl;Peter Bärtsch;Georg H. Merker;Percy Chiu;R. Legro;William L. Nyhan;Sandeep S. Dave;Jürgen Kohlhase;A. Dielis;S. Harvey Mudd;Christian Simon;Oliver Schildgen;S. L. Sternak;G. Mlinarić‐Galinović;Eggert Stockfleth;I. Nindl;Inga Zerr;Mathias Bähr;N. Stankus;Katrin S. Lindenberg;G. Bernhard Landwehrmeyer;Jonas Denecke;S. Katsuragi;B. Grimbacher;C. Woellner;Steven Holland;Christian A. Koch;Michael T. Geraghty;Peter L. M. Jansen;Robert P. Whitehead;Edward M. Brown;Mei Bai;T. Martin;Joaquin Escribano;Victor M. Garca Nieto;Patrick T. S. Ma;Lucia K. Ma;Alexander K. C. Leung;Angelika F. Hahn;M. Nallegowda;Upinderpal Singh;M. Umapathi;Rakesh Kumar;R. Badolato;Benjamin Glaser;R. Schreiber;Daniel Landau;Goo Taeg Oh;C. Kallen;J. Topf;Patrick Murray;Jaime Tejedor;Manish Kumar Varshney;K. Suphapeetiporn;V. Shotelersuk;Bernd Hoppe;Albrecht Hesse;Geoffrey N. Hendy;David E. C. Cole;Charles R. Nolan;H. Shintaku;Hiroshi Ichinose;H. Mankin;G. Uwaifo;Bettina C. Reulecke;Werner Heppt;A. Cryer;Radoslav Tomić;Jesse Roman;J. Rémi;S. Noachtar;M. Nagase;Toshiro Fujita;Á. Cogolludo;Jason X.;Lewis J. Rubin;Manning R. Davis;T. Poduval;Saurabh Chatterjee;H. Gozu;Markus Eszlinger;R. Bircan;J. Lüblinghoff;Julia Lüblighoff;Roland Pfäffle;S. Zhao;Hui;J. Mogensen;R. Kebudi;Sezer Saglam;Michael A. Becker;J. Asplin;R. Gotshall;Hubert Scharnagl;Winfried März;John A. Sayer;Simon H.S. Pearce;James Paparello;P. Klemmer;Abhijit V. Kshirsagar;Patrick T. S. Ma;Lucia K. Ma;Marco Castori;Roswitha Siener;P. Habermehl;M. Knuf;Christoph Michalski;J. Kleeff;Annette Richter;Denis J. Headon;P. Overbeek;Alanna F. Bree;Hendrica Belge;Eva Riveira;Olivier Devuyst;Stefanie Weber;M. Moritz;J. Ayus;Simon H.S. Pearce;Michael P. Whyte;Masafumi Fukagawa;Motoko Tanaka;H. Tenenhouse;A. Gutenberg;Patrizio Caturegli;C. Oswalt;Pirooz Eghtesady;M. Suneja;Christie P. Thomas;H. Sasaki;T. Yukioka;Maurice van Steensel;R. Wu;Ping Wang;G. Feuerstein;Robert R. Ruffolo;H. Jinnah;James C. Harris;Holger K. Eltzschig;A. Grenz - 通讯作者:
A. Grenz
Images in Anesthesia: Detection of a defect pulmonary artery catheter balloon by transesophageal echocardiography
- DOI:
10.1007/bf03021060 - 发表时间:
2003-05-01 - 期刊:
- 影响因子:3.300
- 作者:
Thomas W. Felbinger;Robert W. Lekowski;Stanton K. Shernan;Holger K. Eltzschig - 通讯作者:
Holger K. Eltzschig
Hypoxia signaling in human diseases and therapeutic targets
人类疾病中的缺氧信号通路及治疗靶点
- DOI:
10.1038/s12276-019-0235-1 - 发表时间:
2019-06-20 - 期刊:
- 影响因子:12.900
- 作者:
Jae W. Lee;Junsuk Ko;Cynthia Ju;Holger K. Eltzschig - 通讯作者:
Holger K. Eltzschig
Intraoperative transesophageal echocardiography to assess septic coronary embolism.
术中经食管超声心动图评估脓毒性冠状动脉栓塞。
- DOI:
10.1097/00000542-200212000-00041 - 发表时间:
2002 - 期刊:
- 影响因子:8.8
- 作者:
Holger K. Eltzschig;Robert W. Lekowski;S. Shernan;S. Nedeljkovic;John G. Byrne;Raila Ehlers;S. Aranki - 通讯作者:
S. Aranki
Netrin-1 attenuates acute kidney injury caused by ischemia
- DOI:
10.1016/j.jcrc.2010.08.026 - 发表时间:
2010-12-01 - 期刊:
- 影响因子:
- 作者:
Julee Hong Dalton;Jessica Bauerle;Leslie Cabrera;Jae-Hwan Kim;Carol Aherne;Almut Grenz;Holger K. Eltzschig - 通讯作者:
Holger K. Eltzschig
Holger K. Eltzschig的其他文献
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{{ truncateString('Holger K. Eltzschig', 18)}}的其他基金
Research Training of Anesthesiology Physician-Scientists
麻醉医师科学家的研究培训
- 批准号:
10618804 - 财政年份:2022
- 资助金额:
$ 66万 - 项目类别:
Research Training of Anesthesiology Physician-Scientists
麻醉医师科学家的研究培训
- 批准号:
10333808 - 财政年份:2022
- 资助金额:
$ 66万 - 项目类别:
Targeting MicroRNA miR-122 for the Treatment of Perioperative Liver Injury
靶向 MicroRNA miR-122 治疗围手术期肝损伤
- 批准号:
10598586 - 财政年份:2020
- 资助金额:
$ 66万 - 项目类别:
Targeting MicroRNA miR-122 for the Treatment of Perioperative Liver Injury
靶向 MicroRNA miR-122 治疗围手术期肝损伤
- 批准号:
10366015 - 财政年份:2020
- 资助金额:
$ 66万 - 项目类别:
microRNA miR-147 Dampens Alveolar Epithelial Inflammation During ARDS
microRNA miR-147 抑制 ARDS 期间的肺泡上皮炎症
- 批准号:
10316251 - 财政年份:2020
- 资助金额:
$ 66万 - 项目类别:
microRNA miR-147 Dampens Alveolar Epithelial Inflammation During ARDS
microRNA miR-147 抑制 ARDS 期间的肺泡上皮炎症
- 批准号:
10535454 - 财政年份:2020
- 资助金额:
$ 66万 - 项目类别:
Targeting MicroRNA miR-122 for the Treatment of Perioperative Liver Injury
靶向 MicroRNA miR-122 治疗围手术期肝损伤
- 批准号:
9980672 - 财政年份:2020
- 资助金额:
$ 66万 - 项目类别:
Targeting MicroRNA miR-122 for the Treatment of Perioperative Liver Injury
靶向 MicroRNA miR-122 治疗围手术期肝损伤
- 批准号:
10162584 - 财政年份:2020
- 资助金额:
$ 66万 - 项目类别:
MicroRNA Shuttling during Acute Respiratory Distress Syndrome
急性呼吸窘迫综合征期间的 MicroRNA 穿梭
- 批准号:
9311720 - 财政年份:2017
- 资助金额:
$ 66万 - 项目类别: