Calcineurin Regulates Cardiomyocyte Cell Cycle Through Meis1 and Hoxb13
Calcineurin Regulates Cardiomyocyte Cell Cycle Through Meis1 and Hoxb13
批准号:
10371869
负责人:
Hesham Sadek
金额:
$40.5万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-04-01 至 2022-12-31
关键词:
AddressAdultAgingBindingBirthCDK6-associated protein p18CalcineurinCalcineurin inhibitorCardiacCardiac MyocytesCell CycleCell Cycle ArrestCell Cycle RegulationCellsComplexDNA BindingDNA DamageDataEventFailureFamilyGenetic TranscriptionGoalsGrowthHOX proteinHeartHeart failureHomeodomain ProteinsHumanHyperplasiaHypertrophyInjuryKnockout MiceKnowledgeLinkMediatingMessenger RNAModelingMolecularMyocardial InfarctionMyocardiumNatureNeonatalNuclear Localization SignalNuclear TranslocationPhospho-Specific AntibodiesPlayProcessProtein DephosphorylationProtein phosphataseProteinsRegenerative capacityRegulationResearchResearch PersonnelRoleSerine Phosphorylation SiteSignal TransductionSiteTestingTherapeuticTimeTranscriptional RegulationWithdrawalWorkcalcineurin phosphatasecardiac regenerationcofactordesignexperimental studyhomeodomaininsightinterestloss of functionmechanical loadmouse modeloverexpressionpostnatalregeneration following injuryrepairedresponsetranscription factor
中文摘要
人类心脏衰竭的一个主要因素是成人心脏无法自我修复
英文摘要
A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself
following injury. As a result, strategies to induce heart regeneration are of significant interest. Previously, our
group demonstrated that, unlike the adult heart, the early postnatal mammalian heart is capable of
regeneration following injury through proliferation of existing cardiomyocytes. We have shown that Meis1, a
TALE family homeodomain protein, promotes postnatal withdrawal from cell cycle by activating expression of
the cyclin dependent inhibitors p16 and p21. We, along with other investigators, have gone on to identify a
diversity of additional signaling mechanisms that act to either permit or restrict proliferation (increased
mechanical load, oxygenation, DNA damage response, etc.). This suggests that Meis1 does not work alone,
but must act as part of a network of regulatory processes, although, the molecular mechanisms linking these
processes are largely unknown. Moving forward, the goal of our current proposal is to integrate Meis1-
dependent mechanisms with the wider postnatal signaling network by identifying Meis1 cofactors and
regulators. Specifically, we will focus on defining the functional interaction of Meis1 with its cofactor Hoxb13 in
the postnatal heart and the role played by the Ca2+-activated protein phosphatase calcineurin (CN) in
regulating this interaction and its consequences. The postnatal increase in cardiac load is known to initiate a
signaling cascade that leads to cardiomyocyte hypertrophy and increased contractility. Activation of CN
provides fundamental signals that promote hypertrophic growth of cardiomyocytes. Our preliminary studies
suggest that CN also works in conjunction with a Meis1/Hoxb13 complex to suppress proliferative growth.
Thereby, postnatal activation of CN provides a signal that helps switch the mechanism of cardiac growth from
hyperplastic to hypertrophic. We hypothesize that CN promotes postnatal arrest of cardiomyocyte cell
cycle by mediating nuclear translocation of Meis1 and HoxB13. Our experiments are designed to (1)
examine the role of Hoxb13 as a Meis1 co-factor, (2) define the mechanism of CN regulation of Meis1 and
Hoxb13 function, and (3) test the ability of CN to control postnatal cell cycle and heart regeneration.
These studies will provide fundamental insights into the nature of the coordinating link between the postnatal
increase in cardiac load that drives hypertrophy, and suppression of the heart’s capacity for repair.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Administrative Core (Core A)
-
批准号:10625949
-
项目类别:
-
资助金额:$10.66万
-
财政年份:2023
-
负责人:Hesham Sadek
-
依托单位:
Immune Response-Mediated Regulation of Cardiomyocyte Growth and Renewal
-
批准号:10625948
-
项目类别:
-
资助金额:$216.21万
-
财政年份:2023
-
负责人:Hesham Sadek
-
依托单位:
Supply and Demand: Oxygen and Workload Regulate Cardiomyocyte Proliferation
-
批准号:10572541
-
项目类别:
-
资助金额:$107.18万
-
财政年份:2023
-
负责人:Hesham Sadek
-
依托单位:
Role of cGAS-STING in cardiomyocyte cell cycle regulation
-
批准号:10625952
-
项目类别:
-
资助金额:$49.2万
-
财政年份:2023
-
负责人:Hesham Sadek
-
依托单位:
Project 3 - Role of Proline Metabolism in Regulation of Mammalian Cardiomyocyte Proliferation
-
批准号:10493840
-
项目类别:
-
资助金额:$39.8万
-
财政年份:2022
-
负责人:Hesham Sadek
-
依托单位:
Project 3 - Role of Proline Metabolism in Regulation of Mammalian Cardiomyocyte Proliferation
-
批准号:10677735
-
项目类别:
-
资助金额:$43.0万
-
财政年份:2022
-
负责人:Hesham Sadek
-
依托单位:
Deciphering the Neonatal Cardiac Regenerative Potential and Regulators in Large Animals
-
批准号:10207761
-
项目类别:
-
资助金额:$62.41万
-
财政年份:2019
-
负责人:Hesham Sadek
-
依托单位:
Deciphering the Neonatal Cardiac Regenerative Potential and Regulators in Large Animals
-
批准号:10442732
-
项目类别:
-
资助金额:$62.41万
-
财政年份:2019
-
负责人:Hesham Sadek
-
依托单位:
Regulation of Cardiomyocyte Turnover in the Adult Mammalian Heart
-
批准号:9240660
-
项目类别:
-
资助金额:$40.5万
-
财政年份:2016
-
负责人:Hesham Sadek
-
依托单位:
Regulation of Cardiomyocyte Turnover in the Adult Mammalian Heart
-
批准号:9463489
-
项目类别:
-
资助金额:$40.5万
-
财政年份:2016
-
负责人:Hesham Sadek
-
依托单位:
Role of Meis1 in Regulation of Cardiomyocyte Proliferation
-
批准号:8774983
-
项目类别:
-
资助金额:$7.65万
-
财政年份:2012
-
负责人:Hesham Sadek
-
依托单位:
Role of Meis1 in Regulation of Cardiomyocyte Proliferation
-
批准号:8710336
-
项目类别:
-
资助金额:$50.2万
-
财政年份:2012
-
负责人:Hesham Sadek
-
依托单位:
Role of Meis1 in Regulation of Cardiomyocyte Proliferation
-
批准号:8517813
-
项目类别:
-
资助金额:$37.84万
-
财政年份:2012
-
负责人:Hesham Sadek
-
依托单位:
Role of Meis1 in Regulation of Cardiomyocyte Proliferation
-
批准号:8350363
-
项目类别:
-
资助金额:$39.73万
-
财政年份:2012
-
负责人:Hesham Sadek
-
依托单位:
海外基金