Cardiomyocyte Non-autonomous Factors and Cardiac Regeneration in Large Mammals
大型哺乳动物心肌细胞非自主因素与心脏再生
基本信息
- 批准号:10515862
- 负责人:
- 金额:$ 68.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-09 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdhesivesAdultAngiogenic FactorAntibodiesBiocompatible MaterialsBirthBlood VesselsBlood flowCardiacCardiac MyocytesCase StudyCell CycleCell SurvivalCellsChemicalsClinical ResearchDataEmbryoEndothelial CellsEndotheliumFDA approvedFamily suidaeFishesFunctional disorderFutureGanglionectomyHeartHeart InjuriesHumanHydrogelsInjuryInterventionLinkMaintenanceMammalsMapsMediatingModelingMusMyocardialMyocardial InfarctionMyocardial IschemiaMyocardiumNatural regenerationNeonatalNerve Growth FactorsNeuregulin 1NeuronsNewborn InfantNutrientOperative Surgical ProceduresPatientsPeripheralPharmacologyProteomicsPublicationsRadionuclide ImagingRecombinantsRegenerative capacityRegenerative responseReportingResearchRodentRoleSignal PathwaySmooth Muscle MyocytesStressTestingTherapeuticTherapeutic InterventionVagotomyVascular Endothelial CellVascular Endothelial Growth FactorsVascularizationVentricularVertebratesZebrafishangiogenesisbasebevacizumabcardiac regenerationcardiogenesiscongenital heart disordercytokineenhancing factorexperimental studyfetalheart innervationinduced pluripotent stem cell derived cardiomyocytesischemic injurymouse modelnanoparticle deliveryneonatal micenerve supplyneural networkneurotrophic factornovelparacrinepostnatalregeneration potentialrelating to nervous systemresponsesingle-cell RNA sequencingultrasound
项目摘要
Project Summary
In contrast to the cardiomyocytes (CMs) from lower vertebrates, adult mammalian CMs possess very limited
regenerative potential as a result of cell cycle exit. Interestingly, neonatal mice retain cardiac regenerative
capacity, which is lost by postnatal day 7. We have recently shown that 1-day-old pigs can also regenerate lost
myocardium in response to myocardial infarction (MI). This regeneration is mediated by the proliferation of
preexisting CMs, which does not occur when CMs permanently exit the cell cycle. Mechanisms underlying the
injury-mounted regenerative response especially in large mammals are not fully understood. However,
investigating underlying mechanisms is likely to identify novel targets for future therapeutic interventions.
Recent studies in fish and rodents emphasized the critical importance of vascularization and autonomic
innervation of the regenerating myocardium in zebrafish and neonatal mouse hearts. Besides their function to
provide nutrients, transport metabolites and enable adaptation to stress, it is unknown whether vascular and
neuronal cells, via paracrine interactions, also promote CM proliferation. Intriguingly, our preliminary data
support the idea that soluble factors, e.g., cytokines, secreted from vascular endothelial cells and peripheral
sympathetic neurons significantly stimulate cell cycle activity of co-cultured human induced pluripotent stem
cells-derived CMs, suggesting a critical role of nonmyocyte-CM interactions in modulating CM proliferation in
hearts of larger mammals post injury. In this project, we will exploit the established high regenerative capacity
of the neonatal pig heart model to experimentally address the role of nonmyocytes in injury-induced cardiac
regeneration in large mammals. Two specific aims are proposed. Aim 1 is to define the role of early
revascularization in injury-mounted cardiac regeneration. We will test the hypothesis that early
revascularization is essential for cardiac regeneration in neonatal pigs, and determine whether angiogenesis
promotes cardiac regeneration through the release of pro-myogenic factors from endothelial and/or smooth
muscle cells and/or via de novo formation of functional vessels for maintenance of CM viability. Aim 2 is to
delineate the role of autonomic innervation in injury-mounted cardiac regeneration. We will test the
hypothesis that innervation is essential for post injury cardiac regeneration in neonatal pigs, and determine if
biomaterial-mediated epicardial delivery of angiogenic and neurotrophic factors enhances cardiac regeneration
in neonatal pigs post MI.
项目摘要
与来自低等脊椎动物的心肌细胞(CM)相比,成年哺乳动物CM具有非常有限的
再生潜力作为细胞周期退出的结果。有趣的是,新生小鼠保留了心脏再生能力,
能力,这是失去了出生后第7天。我们最近已经证明,1天大的猪也可以再生失去的
心肌梗死(MI)。这种再生是由细胞增殖介导的。
预先存在的CM,当CM永久退出细胞周期时不会发生。机制研究
特别是在大型哺乳动物中损伤引起的再生反应尚未完全了解。然而,在这方面,
研究潜在的机制有可能为未来的治疗干预确定新的靶点。
最近在鱼类和啮齿类动物中的研究强调了血管化和自主神经系统的重要性。
斑马鱼和新生小鼠心脏再生心肌的神经支配。除了它们的功能,
提供营养物质,运输代谢物,使适应压力,这是未知的,是否血管和
神经元细胞通过旁分泌相互作用也促进CM增殖。有趣的是,我们的初步数据
支持可溶性因子的观点,例如,细胞因子,由血管内皮细胞和外周血
交感神经元显著刺激共培养的人诱导多能干细胞的细胞周期活性
细胞来源的CM,表明非肌细胞CM相互作用在调节CM增殖中的关键作用,
大型哺乳动物受伤后的心脏。在这个项目中,我们将利用现有的高再生能力
的新生猪心脏模型,以实验方式解决非肌细胞在损伤诱导的心脏
大型哺乳动物的再生提出了两个具体目标。目标1:确定早期
血管重建在损伤性心脏再生中的作用。我们将检验早期
血管重建是新生猪心脏再生所必需的,并决定血管生成是否
通过从内皮和/或平滑释放促肌生成因子来促进心脏再生
肌细胞和/或通过从头形成功能性血管以维持CM活力。目标二是
描述自主神经支配在损伤后心脏再生中的作用。我们将测试
假设神经支配是新生猪损伤后心脏再生所必需,并确定
生物材料介导的血管生成和神经营养因子的心外膜递送增强心脏再生
在MI后的新生猪中。
项目成果
期刊论文数量(0)
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{{ truncateString('Wuqiang Zhu', 18)}}的其他基金
Cardiomyocyte Non-autonomous Factors and Cardiac Regeneration in Large Mammals
大型哺乳动物心肌细胞非自主因素与心脏再生
- 批准号:
10680563 - 财政年份:2022
- 资助金额:
$ 68.45万 - 项目类别:
Myocardial Repair with a Novel Engineered Cardiac Muscle Patch
使用新型工程心肌补片修复心肌
- 批准号:
10229464 - 财政年份:2019
- 资助金额:
$ 68.45万 - 项目类别:
Myocardial Repair with a Novel Engineered Cardiac Muscle Patch
使用新型工程心肌补片修复心肌
- 批准号:
10471216 - 财政年份:2019
- 资助金额:
$ 68.45万 - 项目类别:
Myocardial Repair with a Novel Engineered Cardiac Muscle Patch
使用新型工程心肌补片修复心肌
- 批准号:
10002275 - 财政年份:2019
- 资助金额:
$ 68.45万 - 项目类别:
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