Skeletal Muscle and Vascular Remodeling in Peripheral Artery Disease
周围动脉疾病中的骨骼肌和血管重塑
基本信息
- 批准号:9335975
- 负责人:
- 金额:$ 45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-01 至 2018-10-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAffectBenignBlood VesselsCell CountCell Differentiation processCell ProliferationCell fusionCell physiologyCellsCessation of lifeClinicalDevelopmentDifferentiation AntigensDiseaseEndothelial CellsEventGenesGenetic Predisposition to DiseaseGenetic studyGoalsGrowthHumanHuman GeneticsIn VitroInbred BALB C MiceIndividualInjuryIntermittent ClaudicationIschemiaKDR geneLeadLimb structureMediatingModelingMorphologyMouse StrainsMusMuscleMuscle CellsMuscle FibersMuscle functionNatural regenerationNecrosisPECAM1 genePatientsPatternPerfusionPeripheral arterial diseasePhenotypePhysiologicalPopulationPredispositionProcessReceptor SignalingRecombinant adeno-associated virus (rAAV)ResearchResistanceRiskRoleSamplingSignal TransductionSkeletal MuscleStem cellsSyndromeTestingTissuesVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth FactorsVascular blood supplyVascular remodelingclinical phenotypehuman morbidityhuman mortalityin vivoin vivo regenerationlimb amputationmouse modelmuscle necrosismuscle regenerationneovascularizationnovelparacrinepreventpublic health relevancereceptorresponsesatellite celltherapeutic targetvascular contributions
项目摘要
DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) is a major cause of human morbidity and mortality. Evidence suggests that the most severe manifestation of PAD, critical limb ischemia (CLI), is clinically distinct from the more benign syndrome of intermittent claudication (IC). In mice, the propensity to develop CLI-like tissue necrosis is strain- dependent. Both susceptible (BALB/c) and resistant (C57BL/6) strains have been identified, suggesting that a similar genetic susceptibility exists in humans. Human genetic studies have demonstrated linkages to PAD, however the mechanisms that predispose to CLI vs. IC remain unknown. One reason for this may be that the vast majority of studies examining susceptibility to tissue necrosis in limb ischemia have focused on the vasculature. However, we have found that the skeletal muscle cell response, particularly that of skeletal muscle progenitor cells (MPCs), is a key determinant of tissue necrosis after limb ischemia in mice and susceptibility to CLI in humans. Moreover, our findings provide a novel mechanistic model that accounts for the role of known modulators of PAD, such as VEGF, in the development of CLI. In preliminary studies, we have developed a murine model of subacute limb ischemia that leads to muscle necrosis similar to that seen in humans with CLI, and we have demonstrated that: 1) in this model, but not in acute ischemia, mice develop large, mature neovessels in the non-ischemic limb; 2) these vessels contain cells that co-express the MPC marker Pax7 together with CD31, suggesting that MPCs can differentiate into endothelial cells (ECs); 3) ablation of Pax7+ MPCs results in dramatic tissue necrosis, even in necrosis-resistant mouse strains; 4) expression of the VEGF receptor VEGFR-2 on MPCs is induced by ischemia in necrosis-resistant but not necrosis-susceptible mice; 5) VEGF induces MPC proliferation and differentiation; and 6) loss of VEGFR-2 in MPCs in vivo results in deficient muscle regeneration. Taken together, these findings suggest a model in which MPCs, in response to VEGF stimulation, incorporate into new blood vessels to support tissue perfusion and protect muscle cells from ischemic injury. In addition, VEGF promotes MPCs' known direct contribution to muscle regeneration. Thus, we hypothesize that VEGF receptor signaling in endogenous muscle progenitor cells mediates both skeletal muscle neovascularization and myofiber regeneration after limb ischemia in order to limit muscle necrosis. To investigate this hypothesis, our Specific Aims are to: 1. Determine if MPC VEGF receptors are required for neovascularization and muscle regeneration in vivo. 2. Determine if paracrine VEGF signaling is required for MPC-mediated neovascularization in vivo. 3. Determine if MPC VEGF receptors are required for ischemic MPC proliferation, survival, and differentiation in vitro, and if MPCs are similarly affected in patients with CLI.
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher D Kontos其他文献
Christopher D Kontos的其他文献
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{{ truncateString('Christopher D Kontos', 18)}}的其他基金
Medical Scientist Training Program Training Grant
医学科学家培训计划培训补助金
- 批准号:
10411303 - 财政年份:2022
- 资助金额:
$ 45万 - 项目类别:
Medical Scientist Training Program Training Grant
医学科学家培训计划培训补助金
- 批准号:
10647684 - 财政年份:2022
- 资助金额:
$ 45万 - 项目类别:
TIE2 Activation for the Treatment of Chemical-Induced Acute Lung Injury
TIE2 激活治疗化学引起的急性肺损伤
- 批准号:
9753248 - 财政年份:2017
- 资助金额:
$ 45万 - 项目类别:
TIE2 Activation for the Treatment of Chemical-Induced Acute Lung Injury
TIE2 激活治疗化学引起的急性肺损伤
- 批准号:
9352549 - 财政年份:2017
- 资助金额:
$ 45万 - 项目类别:
Skeletal Muscle and Vascular Remodeling in Peripheral Artery Disease
周围动脉疾病中的骨骼肌和血管重塑
- 批准号:
8887762 - 财政年份:2015
- 资助金额:
$ 45万 - 项目类别:
Skeletal Muscle and Vascular Remodeling in Peripheral Artery Disease
周围动脉疾病中的骨骼肌和血管重塑
- 批准号:
8903576 - 财政年份:2014
- 资助金额:
$ 45万 - 项目类别:
Muscle-Resident Stem Cells for Angiogenesis and Vascular Maturation in PAD
用于 PAD 血管生成和血管成熟的肌肉驻留干细胞
- 批准号:
8707552 - 财政年份:2013
- 资助金额:
$ 45万 - 项目类别:
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