Extracellular matrix regulation of differentiation via modulation of ILK: application to 3D bioprinting of cardiac tissue
通过调节 ILK 进行细胞外基质分化调节:在心脏组织 3D 生物打印中的应用
基本信息
- 批准号:10001078
- 负责人:
- 金额:$ 45.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:3-Dimensional3D PrintAccountingActivities of Daily LivingAcuteAddressAdultArteriesBehaviorBiochemistryBiologicalBiological ModelsBioreactorsBlood VesselsCardiacCardiac MyocytesCardiac developmentCardiovascular DiseasesCardiovascular PhysiologyCause of DeathCell Differentiation processCellsCessation of lifeChemicalsChronicCollagen Type ICore FacilityCouplesCyclin-Dependent Kinase Inhibitor 3DependenceDepositionDeveloped CountriesDimensionsDisease modelDrug ScreeningElementsEndothelial CellsEndotheliumEngineeringEventExtracellular MatrixExtracellular Matrix ProteinsFibronectinsFocal Adhesion Kinase 1Focal AdhesionsFormulationGene ExpressionGenerationsGenesGenetic TranscriptionGoalsHeartHeart TransplantationHumanIn VitroIndividualInjuryIntegrinsLaboratoriesLigationLinkLiteratureMass Spectrum AnalysisMediatingMesodermMolecularMotivationMusMyocardialMyocardial tissueMyocarditisMyocardiumNatural regenerationNutrientOutcomeOxygenPathway interactionsPerfusionPluripotent Stem CellsPrintingProteinsRNA InterferenceRegulationResearchSignal PathwaySignal TransductionSpatial DesignTechnologyTestingTherapeuticThickTimeTissue EngineeringTissuesToxicity TestsTranscriptional ActivationUnited Statesarteriolebasebeta cateninbioprintingcell behaviorcell typedesignglycogen synthase kinase 3 beta inhibitorin vivoinduced pluripotent stem cellinnovationinsightintegrin-linked kinasekinase inhibitormatrigelmechanical forcemeetingsmuscle formoptical imagingorgan regenerationprogramsstem cell differentiationstem cellstissue repairtooltranscription factortrend
项目摘要
PROJECT SUMMARY
The primary objective of this proposal is to couple a) mechanistic insight relating differentiation outcomes to
ECM engagement via intracellular signaling events triggered at the focal adhesion (FA), with b) 3D printing of
ECM and ECM-associated proteins as a means to direct cell distribution with maturation and thereby enable
fabrication of thick, functional cardiac tissue. The proposal is significant as it has the potential to generate
replacement tissues and even heart grafts for individuals suffering from acute and chronic injury to the heart. It
is the first of its kind to address the conundrum of the apparent uniformity of the focal adhesion relative to the
myriad of different ECM/integrin combinations and the corresponding variety of cell behaviors that emerge from
ECM engagement. It does so by proposing that elements of the FA, namely integrin linked kinase (ILK) and
associated phosphatase, act as sensitive rheostats that can be co-opted to yield desired behavior. Here, the
desired behavior is cardiac differentiation, and the innovation is the utilization of optimized ECM formulations
as bioinks to create 3D cardiac tissue mimics (3DCTM) capable of directing cell distribution of multiple cell
types with differentiation. This concept is feasible as the Ogle laboratory has long-studied the biochemistry of
the ECM and stem cell behaviors associated with ECM engagement, and the McAlpine laboratory has focused
on 3D printing of functional materials for a range of applications, from biological to electronic and the merger of
these materials. These groups will also interface with expertise of the Kamp lab with respect to their recent
generation of induced cardiac progenitor cells (iCPCs) to populate the 3DCTM, the Provenzano lab to assist
with molecular mechanisms associated with FA formation, the Garry lab to assist with bioreactor
implementation, the Zhang lab to add cardiovascular physiology expertise, and the Talkachova lab to assist
with optical imaging to assess function of the 3DCTM and core facilities for mass spectrometry of ECM
components and gene editing tools for modulating ILK activity. Together, this expertise will be funneled toward
meeting the primary objective of the proposal via the following aims: 1) determine whether activation of
integrin-linked kinase (ILK) of focal adhesions or costameres couples integrin activation to β-catenin activation
via GSK3β to enable expression of genes associated with cardiomyocyte specification, 2) use 3D ECM-based
model systems to identify ECM formulations supportive of endothelial differentiation and assess ILK
dependence, and 3) use ECM-based 3D printing to modulate differentiation of cardiac cell types spatially in a
cardiac tissue mimic. The motivation for this concept was based on extensive literature search, and results
from our own experimentation; the approach was designed to insure that the interpretations of the results are
subject to minimal bias and the hypotheses posed are truly tested.
项目总结
项目成果
期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Implementing Biological Pacemakers: Design Criteria for Successful.
- DOI:10.1161/circep.121.009957
- 发表时间:2021-10
- 期刊:
- 影响因子:0
- 作者:Komosa ER;Wolfson DW;Bressan M;Cho HC;Ogle BM
- 通讯作者:Ogle BM
Laminin 411 mediates endothelial specification via multiple signaling axes that converge on β-catenin.
- DOI:10.1016/j.stemcr.2022.01.005
- 发表时间:2022-03-08
- 期刊:
- 影响因子:5.9
- 作者:Hall, Mikayla L.;Givens, Sophie;Santosh, Natasha;Iacovino, Michelina;Kyba, Michael;Ogle, Brenda M.
- 通讯作者:Ogle, Brenda M.
Kinases of the Focal Adhesion Complex Contribute to Cardiomyocyte Specification.
局灶性粘附复合物的激酶有助于心肌细胞规范。
- DOI:10.3390/ijms221910430
- 发表时间:2021-09-28
- 期刊:
- 影响因子:5.6
- 作者:Robert S;Flowers M;Ogle BM
- 通讯作者:Ogle BM
Body builder: from synthetic cells to engineered tissues.
- DOI:10.1016/j.ceb.2018.04.010
- 发表时间:2018-10
- 期刊:
- 影响因子:7.5
- 作者:Hu S;Ogle BM;Cheng K
- 通讯作者:Cheng K
Cardiac Extracellular Matrix Modification as a Therapeutic Approach.
- DOI:10.1007/978-3-319-97421-7_7
- 发表时间:2018
- 期刊:
- 影响因子:0
- 作者:Hall ML;Ogle BM
- 通讯作者:Ogle BM
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Michael McAlpine其他文献
Michael McAlpine的其他文献
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{{ truncateString('Michael McAlpine', 18)}}的其他基金
Extracellular matrix regulation of differentiation via modulation of ILK: application to 3D bioprinting of cardiac tissue
通过调节 ILK 进行细胞外基质分化调节:在心脏组织 3D 生物打印中的应用
- 批准号:
9301966 - 财政年份:2017
- 资助金额:
$ 45.21万 - 项目类别:
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