Investigating the Roles of APJ, Hypoxia, and SOX17 in the Development of Coronary Vessels
Investigating the Roles of APJ, Hypoxia, and SOX17 in the Development of Coronary Vessels
批准号:
10291709
负责人:
Bikram Sharma
金额:
$42.9万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-09-01 至 2024-08-31
关键词:
APLN geneAcademic Research Enhancement AwardsAddressAdultBlood VesselsCause of DeathCell Culture TechniquesCellular biologyCoronaryCoronary ArteriosclerosisCoronary VesselsCoronary arteryCuesDataDefectDevelopmentDiseaseEmbryoEmbryonic HeartEndocardiumEndothelial CellsEndotheliumEpicardiumFetal DiseasesFutureG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGoalsGrowthHeartHeart failureHypoxiaHypoxia Inducible FactorIn VitroKnock-outKnowledgeLaboratoriesLigandsMediatingModelingModernizationMolecularMolecular BiologyMolecular Biology TechniquesMusMyocardial InfarctionMyocardiumNatural regenerationPathogenesisPathway interactionsPeptidesPopulationProceduresProcessReceptor ActivationReceptor SignalingRegulationResearchResearch TrainingRoleSOX17 geneScienceSignal TransductionSourceStructure of sinus venosus of fetusStudentsSystemTherapeuticTimeTrainingTransgenic MiceTreesUniversitiesVEGFC geneVascular Endothelial Growth FactorsWorkangiogenesiscareercell behaviorclinically significantdesigneffective therapyexperienceexperimental studygain of functiongraduate studenthigh schoolin vivoinnovationloss of functionmigrationmouse modelmyocardial hypoxiapreventprogenitorreceptorrepairedresearch and developmentresponsestem cell populationstem cellstissue culturetranscription factorundergraduate studentvenous sinus
中文摘要
项目总结
英文摘要
Project Summary
This proposal uses transgenic mouse models and modern cell and molecular biology approaches to characterize
the roles of APJ, hypoxia, and SOX17 in the regulation of coronary vessel formation. Coronary artery disease is
one of the leading causes of death worldwide and still lacks effective treatment. Therefore, understanding how
these vessels form for the first time in the embryos and dissecting their cellular and molecular mechanisms can
be valuable in designing appropriate therapeutics. From studies in mice, it is known that coronary vessels are
formed from multiple endothelial progenitors namely proepicardium, sinus venosus, and endocardium. Although
the progenitor stem cells for the origin of coronary vessel formation is identified, a significant lack of knowledge
exist on what cues guide these progenitors to form coronary vascular tree. In this context, we have identified
molecular pathways that selectively impact coronary growth from sinus venosus and endocardium. Apelin
receptor (commonly known as APJ), a G-protein coupled receptor, is found to be important for the sinus venous
derived progenitor pathway whereas myocardial hypoxia is found to be potentially important for the endocardium
derived progenitor pathway of coronary vessel formation. Furthermore, a transcription factor SOX17 is also found
to be expressed by activated endocardial progenitors, suggesting a role for SOX17 during coronary
angiogenesis. At this point, we know very little on how APJ, hypoxia inducible factor-1alpha (HIF-1alpha), and
SOX17 regulate coronary angiogenesis. APJ is activated by two peptide ligands, ELABELA (aliases: APELA,
TODDLER) and APELIN, which are both expressed in embryonic hearts. It is not clear how APJ signaling from
these two ligands coordinate the progression of coronary vessel formation from sinus venosus progenitor
pathway. This proposal is aimed at unraveling the unknowns of APJ, Hypoxia, and SOX17 mediated
regulation of coronary vessel formation. In Aim 1, we hypothesize that ELABELA/APJ and APELIN/APJ
signaling primes sinus venosus derived coronary progenitors to respond to angiogenic cues such as VEGFC
(in the epicardium) and VEGF-A (in the myocardium) respectively. In Aim 2, we hypothesize that
myocardial hypoxia activates SOX17 expression in endocardial progenitors, and SOX17 promotes coronary
angiogenesis. The experiments proposed in this study are highly appropriate for high school, undergraduate,
and graduate students and these students will be engaged in every stage of the project, allowing them to
obtain authentic research experience with innovative approaches including transgenic mouse models (gain-
of-function and loss-of-function models), cell and tissue culture systems, and modern cell and molecular
biology techniques.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1016/j.ydbio.2023.04.003
发表时间:
2023-04
期刊:
Developmental biology
影响因子:
2.7
作者:
[K. Baral;Gaetano D'Amato;Bryce Kuschel;Frank Bogan;Brendan W. Jones;Colton L. Large;Jeffery D. Whatley;K. Red-Horse;B. Sharma]
通讯作者:
K. Baral;Gaetano D'Amato;Bryce Kuschel;Frank Bogan;Brendan W. Jones;Colton L. Large;Jeffery D. Whatley;K. Red-Horse;B. Sharma