Sculpting the atherosclerotic plaque by neurotrophins
Sculpting the atherosclerotic plaque by neurotrophins
批准号:
7406109
负责人:
BARBARA L HEMPSTEAD
金额:
$42.43万
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-04-01 至 2008-03-31
关键词:
AnimalsApolipoprotein EApoptosisApoptoticArterial Fatty StreakBindingBiologicalBlood VesselsBrain-Derived Neurotrophic FactorCardiacCell DeathCellsCessation of lifeChemotaxisClassCleaved cellCodeDevelopmentEndopeptidasesEndothelial CellsExonsFamilyGoalsGrowth FactorHematopoieticHumanIn VitroInjuryLesionLigandsLocalizedMatrix MetalloproteinasesMediatingModelingMusNGFR ProteinNerve Growth Factor 1Nerve Growth Factor PathwayNeuronsNeurotrophin 3OutcomePeptide HydrolasesPlasminPlasminogenProtein OverexpressionReceptor Protein-Tyrosine KinasesRecruitment ActivityResistanceRoleSiteSmooth Muscle MyocytesSystemTechniquesTumor Necrosis Factor ReceptorVascular remodelingbrain-derived neurotrophic factor precursorfemoral arterygene replacementin vivomacrophagemembermonocytemutantneurotrophic factorreceptorresponse to injurytranscriptional coactivator p75
中文摘要
动脉粥样硬化的发展在一定程度上受生长因子的局部表达调控,生长因子促进造血细胞和血管平滑肌细胞向新生内膜募集。我们之前证明了神经营养因子及其受体,trk受体酪氨酸激酶家族和p75神经营养因子受体(p75NTR)在动脉粥样硬化病变中高度表达。神经营养因子在调节血管发育和调节血管损伤反应中的三种特定作用已被确定:
英文摘要
The development of atheroma is regulated in part by the localized expression of growth factors that promote the recruitment of hematopoietic cells as well as vascular smooth muscle cells into the neointima. We previously demonstrated that the neurotrophins and their receptors, the trk family of receptor tyrosine kinases and the p75 neurotrophin receptor (p75NTR), are highly expressed in atherosclerotic lesions. Three specific roles for the neurotrophins in regulating vessel development and in modulating the vascular response to injury have been identified:
(1) neurotrophin-mediates survival of Trk B-expressing cardiac endothelial cells (2) neurotrophin-induced recruitment of Trk A and Trk B-expressing vascular smooth muscle cells to the developing neointima following injury; (3) neurotrophin-induced activation of p75NTR-expressing smooth muscle cells in the neointima induces apoptotic cell death. The paradox of neurotrophin actions in the vasculature, mediating both pro-survival and pro-death outcomes, has recently been clarified by our identification that the pro-forms of the neurotrophins selectively bind to the proapoptotic p75NTR, whereas the mature ligand selectively activates the chemotactic and survival promoting Trk receptors. Our preliminary studies indicate that both the pro- and mature forms of the neurotrophins NGF and BDNF are expressed in human atherosclerotic lesions and atheroma from murine models, and that selective MMPs and
plasmin can cleave pro-forms to mature forms. The long term goals of this project are to understand how the differential expression of pro- and mature forms of neurotrophins regulate the dynamics of lesion formation and vascular remodeling. Studies in Specific Aim 1 will define the spatial and temporal expression of the pro- and mature forms of the neurotrophins in human lesions and in murine models of atheromata formation and correlate their expression with the co-ordinate expression of p75NTR and Trk receptors, as well as MMPs and components of the
plasminogen protease system. Studies in Specific Aim 2 will identify the biological actions of the pro-neurotrophins on vascular smooth muscle cells, monocytes/macrophages and endothelial cells using in vitro analysis of chemotaxis, survival and apoptosis and compare them to the actions of the mature neurotrophins. Finally, in Specific Aim 3, we will genetically dissect the actions of the pro-neurotrophins from mature neurotrophins in lesion formation in vivo by
replacing the native BDNF coding exon with a cleavage resistant mutant to generate only pro-BDNF. The effects of pro-BDNF overexpression in murine models of vascular injury will be assessed. The results of these studies may identify unique targets to regulate the microenvironment of the developing atheroma.
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会议论文
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资助金额:$36.02万
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财政年份:2009
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Regulating BDNF Action in Postnatal Development.
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资助金额:$34.75万
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财政年份:2009
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负责人:BARBARA L HEMPSTEAD
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Regulating BDNF Action in Postnatal Development.
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批准号:7565724
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资助金额:$36.75万
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财政年份:2009
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负责人:BARBARA L HEMPSTEAD
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Functional analysis of variant BDNF (Val66Met)
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批准号:8914167
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财政年份:2005
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负责人:BARBARA L HEMPSTEAD
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依托单位:
Gordon Conference on Neurotrophic Factors (2003,2005)
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批准号:6892371
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项目类别:
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资助金额:$3.3万
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财政年份:2003
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负责人:BARBARA L HEMPSTEAD
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依托单位:
Gordon Conference on Neurotrophic Factors (2003,2005)
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批准号:6751906
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项目类别:
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资助金额:$0.0万
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财政年份:2003
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负责人:BARBARA L HEMPSTEAD
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依托单位:
Gordon Conference on Neurotrophic Factors (2003,2005)
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批准号:6597988
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项目类别:
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资助金额:$3.3万
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财政年份:2003
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负责人:BARBARA L HEMPSTEAD
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依托单位:
Core--Histotechnology
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批准号:6600057
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资助金额:$21.46万
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财政年份:2002
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负责人:BARBARA L HEMPSTEAD
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依托单位:
Intracellular signals and smooth muscle cell migration
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批准号:6664600
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资助金额:$15.75万
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财政年份:2002
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负责人:BARBARA L HEMPSTEAD
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依托单位:
Neurotrophins in angiogenesis
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批准号:6670768
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项目类别:
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资助金额:$29.04万
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财政年份:2002
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负责人:BARBARA L HEMPSTEAD
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依托单位:
INTRACELLULAR SIGNALS MEDIATING SMOOTH MUSCLE CELL MIGRATION
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批准号:6336654
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项目类别:
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资助金额:$28.8万
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财政年份:2000
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依托单位:
INTRACELLULAR SIGNALS MEDIATING SMOOTH MUSCLE CELL MIGRATION
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资助金额:$28.8万
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财政年份:1999
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负责人:BARBARA L HEMPSTEAD
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依托单位:
NEUROTROPHINS AND CARDIOGENESIS
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项目类别:
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资助金额:$26.08万
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财政年份:1998
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依托单位:
NEUROTROPHINS AND CARDIOGENESIS
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资助金额:$24.57万
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财政年份:1998
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负责人:BARBARA L HEMPSTEAD
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依托单位:
NEUROTROPHINS AND CARDIOGENESIS
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资助金额:$28.24万
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财政年份:1998
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负责人:BARBARA L HEMPSTEAD
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NEUROTROPHINS AND CARDIOGENESIS
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资助金额:$29.04万
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财政年份:1998
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负责人:BARBARA L HEMPSTEAD
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NEUROTROPHINS AND CARDIOGENESIS
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