Understanding fibrin-mediated immunomodulation in wound healing
了解伤口愈合中纤维蛋白介导的免疫调节
基本信息
- 批准号:10237311
- 负责人:
- 金额:$ 5.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-25 至 2023-08-24
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffectAnti-Inflammatory AgentsB-LymphocytesBiological AssayBiological Response ModifiersBiomedical EngineeringBone MarrowCXCL13 geneCellsCicatrixClinicalCoagulation ProcessCoculture TechniquesDataDebridementDiabetes MellitusDiabetic Foot UlcerEconomic BurdenEffector CellEngineeringExtracellular MatrixFibrinFibroblastsFibrosisFlow CytometryForeign BodiesGelHistologyHydrogelsImmuneImmunologyImpaired wound healingIn VitroIncidenceInflammationInflammatoryMeasuresMechanicsMediatingMediator of activation proteinMetabolic syndromeModelingMusMyofibroblastNatural regenerationOperative Surgical ProceduresOutcomePatient CarePhasePhenotypePhysiologicalPopulationPublishingRoleSignal TransductionSkin wound healingSmooth Muscle Actin Staining MethodSpottingsStereotypingStimulusTestingTherapeuticThickTraumatic injuryWorkWound modelsacute woundarginasebasecell typechronic woundcostcytokinedesignefficacy testinghealingimmunomodulatory therapiesimmunoregulationimprovedin vivoinnovationmacrophagemouse modelneutrophilnovel therapeuticsparacrineresponsescaffoldskin woundtissue regenerationtooltranscriptome sequencingwoundwound carewound healing
项目摘要
PROJECT SUMMARY
The incidence of acute and chronic wounds from surgery, traumatic injury, diabetes, and metabolic syndrome is
on the rise, affecting over three million people in the US alone and costing tens of billions of dollars a year.
Successful wound healing progresses through coagulation/inflammation, proliferation, and remodeling phases,
culminating in tissue regeneration and/or contraction and scarring. Macrophages are essential mediators of
progression through these stages, and responsive to external therapeutic modulation. Yet, the soluble and
mechanical factors mediating macrophage interactions with these materials and other wound effectors remain
largely unknown. I propose to use immunology and bioengineering approaches to improve our tools and work to
fill this unmet clinical need. Our previous work demonstrated that fibrin, a major component of the provisional
extracellular matrix, skews murine bone marrow derived macrophages (BMDM) towards an anti-inflammatory
phenotype in vitro, suppressing the stereotyped cytokine response to potent inflammatory stimuli, including LPS.
Preliminary data from 5 mm full-thickness skin wounds in mice showed anti-inflammatory skew in the wound,
measured by Arginase, iNOS, and YAP expression in macrophages, and diminished myofibroblast marker alpha
smooth muscle actin (aSMA) with fibrin treatment, suggesting a role for macrophage-myofibroblast interactions
in the wound. Additionally, both soft (1.2 kPa) and stiff (840kPa) gels have been shown to increase macrophage
secretion of inflammatory cytokines seen in the stereotyped foreign body response (e.g. TNFa), with intermediate
stiffness showing lower secretion, indicating a mechanical sweet spot for immunomodulation. I propose to
engineer fibrin-PEG hydrogels, mechanically optimized for macrophage immunomodulatory capacity, and apply
them to in vitro cocultures to determine macrophage-fibroblast-fibrin interaction dynamics and test the hypothesis
that fibrin hydrogels of moderate stiffness (~140 kPa) will best promote anti-inflammatory macrophage
phenotype, facilitating decreased myofibroblast contractility. I also aim to define the mechanisms by which fibrin
hydrogels modulate macrophage phenotype to achieve wound healing and regeneration in vivo, using a full
thickness skin wound model in wild type, and selective immune cell depletions models (macrophage- MAFIA,
clodrosome;; neutrophil- anti-GR1, B-cell-anti-CXCL13). I will use histology, flow cytometry, and RNA-seq to test
the hypothesis that fibrin-PEG hydrogels of moderate stiffness (~140 kPa) will accelerate wound resolution and
tissue regeneration by promoting anti-inflammatory macrophage phenotype. Understanding the mediators of
fibrin-enhanced wound healing will help us better understand physiologic wound repair, and will lay the
groundwork for rational design of novel therapeutics, and better wound care for patients.
项目摘要
手术、创伤性损伤、糖尿病和代谢综合征引起的急性和慢性伤口的发病率是
仅在美国就有超过300万人受到影响,每年造成数百亿美元的损失。
成功的伤口愈合经历凝血/炎症、增殖和重塑阶段,
最终导致组织再生和/或收缩和瘢痕形成。巨噬细胞是
通过这些阶段的进展,并响应外部治疗调制。然而,可溶性和
介导巨噬细胞与这些材料和其它伤口效应物相互作用的机械因素仍然存在
我建议使用免疫学和生物工程方法来改进我们的工具,
我们以前的工作表明,纤维蛋白,临时的主要成分,
细胞外基质,使小鼠骨髓源性巨噬细胞(BMDM)倾向于抗炎
表型,抑制定型的细胞因子对强效炎症刺激,包括LPS的反应。
来自小鼠5 mm全厚皮肤伤口的初步数据显示伤口中的抗炎性偏斜,
通过巨噬细胞中精氨酸酶、iNOS和雅普表达测量,并减少肌成纤维细胞标记物α
平滑肌肌动蛋白(aSMA)与纤维蛋白处理,表明巨噬细胞-成肌纤维细胞相互作用的作用
此外,软(1.2 kPa)和硬(840 kPa)凝胶均显示出增加巨噬细胞
在定型异物反应中观察到的炎性细胞因子分泌(例如TNF α),
硬度显示较低的分泌,表明免疫调节的机械甜蜜点。我建议
工程化纤维蛋白-PEG水凝胶,针对巨噬细胞免疫调节能力进行了机械优化,
将它们与体外共培养物共培养,以确定巨噬细胞-成纤维细胞-纤维蛋白相互作用的动力学,
中等硬度(~140 kPa)的纤维蛋白水凝胶最能促进抗炎巨噬细胞
表型,促进肌成纤维细胞收缩性下降。我的目的也是确定机制,纤维蛋白
水凝胶调节巨噬细胞表型,以实现体内伤口愈合和再生,使用全
野生型的厚皮肤创伤模型和选择性免疫细胞耗竭模型(巨噬细胞-巨噬细胞MAFIA,
clodrosome;嗜中性粒细胞-clod anti-clod GR 1,B-clod cell-clod anti-clod CXCL 13)。
中等硬度(~140 kPa)的纤维蛋白-PEG水凝胶将加速伤口消退的假设,
组织再生通过促进抗炎巨噬细胞表型。了解介质,
纤维蛋白酶促进伤口愈合将有助于我们更好地理解生理性伤口修复,
为合理设计新疗法和更好地护理患者伤口奠定基础。
项目成果
期刊论文数量(0)
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Raji Nagalla其他文献
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{{ truncateString('Raji Nagalla', 18)}}的其他基金
Understanding fibrin-mediated immunomodulation in wound healing
了解伤口愈合中纤维蛋白介导的免疫调节
- 批准号:
10017645 - 财政年份:2019
- 资助金额:
$ 5.1万 - 项目类别:
Understanding fibrin-mediated immunomodulation in wound healing
了解伤口愈合中纤维蛋白介导的免疫调节
- 批准号:
10471829 - 财政年份:2019
- 资助金额:
$ 5.1万 - 项目类别:
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