CHEMOKINES AND IMMUNE CELLS IN HIND LIMB ISCHEMIA
后肢缺血中的趋化因子和免疫细胞
基本信息
- 批准号:7622550
- 负责人:
- 金额:$ 37.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-09-01 至 2012-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAdipocytesAdjuvantAdjuvant TherapyAfghanistanAmputationAnimalsArteriesBiological AssayBiological Response ModifiersBiologyBlood VesselsBlood capillariesBone MarrowBone Marrow CellsCC chemokine receptor 2CellsChestChimera organismComplexDefectDepositionDevelopmentDirect Lytic FactorsDissectionEndothelial CellsExcisionExclusionExhibitsFatty acid glycerol estersFibrosisFluorescenceGenotypeGoalsGrantGreen Fluorescent ProteinsHealedHematopoieticImmuneImmune responseImmunologyImpairmentInflammationInflammatoryInjection of therapeutic agentInjuryIschemiaKnockout MiceLeadLegLimb SalvageLimb structureMediatingModelingMonocyte Chemoattractant Protein-1MusMuscleNatural regenerationNecrosisOutcomePathologyPatientsPeripheralPhenotypePhysiologyPlayPredispositionProductionProteinsRadiation ChimeraResearchRoleSkeletal MuscleSkeletal muscle injurySmooth Muscle MyocytesSoldierSourceSystemT-LymphocyteTestingTimeTissue EngineeringTissuesTransgenic MiceTransgenic OrganismsTraumaUpper armVascular Endothelial Growth FactorsVeteransWarWild Type MouseWound Healingangiogenesiscapillarycell typechemokinechemokine receptordefined contributiondensitydesignfemoral arteryhealingimprovedin vivoinjuredinnovationirradiationlimb injurymacrophagematrigelmonocytemouse modelmuscle regenerationnovelolder patientprogenitorreceptorregenerativeresearch studyresponserestorationsoft tissuestem cell biologysuccesstissue regeneration
项目摘要
DESCRIPTION (provided by applicant): Muscle regeneration and angiogenesis are important components of limb salvage following traumatic and/or ischemic injury to the extremities. We have demonstrated that knockout mice lacking either monocyte chemotactic protein-1 (MCP-1) or its specific receptor, the CC Chemokine Receptor 2 (CCR2), have impairments in macrophage recruitment and muscle regeneration following ischemic or toxic injury. In addition, CCR2-/- mice exhibit increased adipocyte accumulation in regenerated muscle. Bone marrow (BM) replacement of CCR2 -/- mice with wild type (WT) BM (radiation chimeras) led to increased early macrophage recruitment and normal muscle regeneration (i.e., recapitulated the phenotype of WT mice). Furthermore, replacing the BM of WT mice with CCR2 -/- BM resulted in decreased macrophage recruitment and impaired muscle regeneration (i.e., recapitulated the phenotype of CCR2 -/- mice). This suggests that BM-derived cells modulate the healing responses of muscle and that macrophages are the likely BM-derived cell type that mediates the impaired muscle regeneration in CCR2 -/- mice. Further studies revealed impaired angiogenesis in CCR2 -/- mice in conjunction with decreased tissue vascular endothelial growth factor (VEGF) compared to WT mice. Interestingly, restoration of VEGF to baseline levels was associated with the development of maximal capillary density in both CCR2 -/- and WT mice. While impaired muscle regeneration in CCR2 -/- mice is attributable to a BM-derived cell, the effects of BM-derived vs. host-derived cells have not been studied in regards to angiogenesis. Our long-term goal is to define the influence of inflammation, including the chemokine system, in angiogenesis and skeletal muscle regeneration. The following 3 specific aims will test the overall hypothesis that the recruitment and activation of BM-derived cells, especially monocytes/macrophages, are essential for angiogenesis, a critical component in skeletal muscle regeneration after injury. 1) Determine the contribution of CCR2 expression in BM-derived vs. non-BM- derived cells on angiogenesis in skeletal muscle after injury, 2) Determine the ex vivo and in vivo influence of the MCP-1/CCR2 axis on angiogenesis and 3) Define the effects of selective and complete monocyte/macrophage ablation prior to muscle injury and sustained throughout the time course of tissue repair on inflammation and angiogenesis after injury. The proposed studies are innovative because they will help define the contribution of BM-derived cells to angiogenesis. The significance of this research is that a better understanding of the mechanisms of skeletal muscle regeneration and angiogenesis could lead to the design of novel primary or adjuvant treatments for improved limb salvage and tissue engineering. PUBLICE HEALTH RELEVANCE: Leg and arm wounds, with large muscle defects and high amputation rates, are common in trauma victims and especially in injured soldiers from the Iraqi/Afghanistan war; new treatments to replace the missing muscle are needed to decrease amputation rates and improve limb function. Our research studies the complex relationships between the multiple cells that are needed to make new muscle, including blood vessels. A better understanding of how new blood vessels help muscle recover from injury could lead to new therapies, including tissue engineering strategies, to help patients recover from these devastating injuries.
描述(申请人提供):肌肉再生和血管生成是肢体创伤和/或缺血性损伤后保肢的重要组成部分。我们已经证明,缺乏单核细胞趋化蛋白-1(MCP-1)或其特异性受体CC趋化因子受体2(CCR2)的基因敲除小鼠,在缺血或中毒损伤后,巨噬细胞募集和肌肉再生方面存在损害。此外,CCR2-/-小鼠在再生肌肉中脂肪细胞积聚增加。用野生型(WT)BM(辐射嵌合体)替换CCR2-/-小鼠的骨髓(BM)导致早期巨噬细胞募集和正常肌肉再生(即概括WT小鼠的表型)增加。此外,用CCR2-/-BM替换WT小鼠的BM会导致巨噬细胞募集减少和肌肉再生受损(即概括了CCR2-/-小鼠的表型)。这表明骨髓来源的细胞调节肌肉的修复反应,巨噬细胞可能是介导CCR2-/-小鼠受损的肌肉再生的骨髓来源细胞类型。进一步的研究发现,与WT小鼠相比,CCR2-/-小鼠的血管生成受损,同时组织血管内皮生长因子(VEGF)减少。有趣的是,在CCR2-/-和WT小鼠中,血管内皮生长因子恢复到基线水平与最大毛细血管密度的发展有关。虽然CCR2-/-小鼠的肌肉再生受损可归因于骨髓来源的细胞,但骨髓来源的细胞与宿主来源的细胞在血管生成方面的作用尚未进行研究。我们的长期目标是确定炎症,包括趋化因子系统,在血管生成和骨骼肌再生中的影响。以下三个特定目标将检验BM来源的细胞,特别是单核/巨噬细胞的招募和激活对血管生成至关重要的总体假设,血管生成是骨骼肌损伤后再生的关键组成部分。1)确定BM来源的细胞与非BM来源的细胞中CCR2的表达对损伤后骨骼肌血管生成的贡献;2)确定MCP-1/CCR2轴在体内外对血管生成的影响;3)确定肌肉损伤前选择性和完全去除单核/巨噬细胞对损伤后炎症和血管生成的影响。拟议的研究具有创新性,因为它们将有助于确定骨髓来源的细胞对血管生成的贡献。这项研究的意义在于,更好地了解骨骼肌再生和血管生成的机制,可以为改进肢体保全和组织工程设计新的初级或辅助治疗方法。与公共卫生相关:腿部和手臂的创伤,有大的肌肉缺陷和高截肢率,在创伤受害者中很常见,特别是在伊拉克/阿富汗战争中受伤的士兵中;需要新的治疗方法来取代缺失的肌肉,以降低截肢率和改善肢体功能。我们的研究研究了多个细胞之间的复杂关系,这些细胞是制造新肌肉所需的,包括血管。更好地了解新血管如何帮助肌肉从损伤中恢复可能会导致新的治疗方法,包括组织工程策略,以帮助患者从这些毁灭性的损伤中恢复。
项目成果
期刊论文数量(0)
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PAULA K SHIREMAN其他文献
PAULA K SHIREMAN的其他文献
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{{ truncateString('PAULA K SHIREMAN', 18)}}的其他基金
Harnessing the power of CTSA-CDRN data networks: Using social determinants of health, frailty and functional status to identify at-risk patients and improve risk adjustment
利用 CTSA-CDRN 数据网络的力量:利用健康、虚弱和功能状态的社会决定因素来识别高危患者并改善风险调整
- 批准号:
10199784 - 财政年份:2018
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Harnessing the power of CTSA-CDRN data networks: Using social determinants of health, frailty and functional status to identify at-risk patients and improve risk adjustment
利用 CTSA-CDRN 数据网络的力量:利用健康、虚弱和功能状态的社会决定因素来识别高危患者并改善风险调整
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MicroRNA Regulation of Macrophage Polarization in Muscle Regeneration
肌肉再生中巨噬细胞极化的 MicroRNA 调节
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8598034 - 财政年份:2011
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MicroRNA Regulation of Macrophage Polarization in Muscle Regeneration
肌肉再生中巨噬细胞极化的 MicroRNA 调节
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8240594 - 财政年份:2011
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MicroRNA Regulation of Macrophage Polarization in Muscle Regeneration
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后肢缺血中的趋化因子和免疫细胞
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$ 37.1万 - 项目类别:
CHEMOKINES AND IMMUNE CELLS IN HIND LIMB ISCHEMIA
后肢缺血中的趋化因子和免疫细胞
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7856125 - 财政年份:2003
- 资助金额:
$ 37.1万 - 项目类别:
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