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.
项目摘要
这项拨款申请的主要目标是针对围手术期心脏保护的昼夜节律。
围手术期心肌缺血再灌注损伤(IRI)和梗死仍然是发病的主要原因
和手术患者的死亡率。然而,经皮冠状动脉介入治疗结合
由于出血风险,抗凝和血小板抑制剂可能不适用于围手术期
从手术部位。寻找新的药理学或介入策略,使心肌更多
抵抗心肌IRI的有害影响对于围手术期和重症监护具有重要意义
药先前的研究表明,心肌IRI的发生遵循昼夜节律模式,
与昼夜节律和缺氧信号之间的相互作用有关。因此,当前的应用是
重点是确定可以作为治疗靶点以抑制心肌IRI的昼夜节律机制。
为了研究心肌IRI的昼夜节律控制,我们建立了小鼠原位心肌IRI模型,
发现在Zeitgeber时间(ZT)8(3 pm)时梗死面积最小,在ZT 20(3am)时梗死面积最大。
暴露于心肌细胞的小鼠左心室风险区域的后续无偏RNA测序
ZT 8与ZT 20的IRI将我们指向核心昼夜节律转录因子Bmal 1。类似地,RNA-seq
上午与下午组接受心脏手术的患者的左心室活检数据
证实BMAL 1是最差异表达的基因。在功能研究中,使用转基因小鼠,
肌细胞特异性缺失Bmal 1(Bmal 1 loxp/loxp肌球蛋白Cre+小鼠),我们观察到完全钝化的
ZT 8的心脏保护作用。免疫共沉淀和质谱鉴定出缺氧-
诱导因子2-α(HIF 2A)作为BMAL 1的结合伴侣。与Bmal 1 loxp/loxp肌球蛋白Cre+小鼠相似,我们
观察到在ZT 8时在Hif 2aloxp/loxp肌球蛋白Cre+小鼠中消除了心脏保护。随后的生化和
生物物理学研究揭示了BMAL 1和HIF 2A之间的直接相互作用,显示出4.5电子密度
与缺氧反应元件(HRE)DNA复合的BMAL 1/HIF 2A异二聚体图谱。最后我们
鉴定了双调蛋白(AREG)作为BMAL 1/HIF 2A异二聚体介导
昼夜节律依赖的心脏保护作用。因此,我们假设BMAL 1和HIF 2A在转录水平上形成了一个转录调控因子。
活性复合物在介导昼夜节律依赖性心脏保护中的关键作用
AREG的规则。我们提出了三个具体的目标来解决这一假设:(1)表征的相互作用
BMAL 1和HIF 2A之间的关系及其在体外缺氧或体内心肌IRI中的功能作用。(2)研究
BMAL 1/HIF 2A-AREG介导昼夜节律依赖性心脏保护的共同靶基因。(3)目标
BMAL 1/HIF 2A用于围手术期心肌IRI期间的心脏保护和原理验证研究。
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
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
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
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: