Autonomous RUNX2 suppression in genetically modified stem cell-derived chondrocytes as a disease modifying therapeutic for PTOA
转基因干细胞衍生软骨细胞中的自主 RUNX2 抑制作为 PTOA 的疾病修饰疗法
基本信息
- 批准号:10574780
- 负责人:
- 金额:$ 19.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-03 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAnti-Inflammatory AgentsArthralgiaBiologicalBiomedical EngineeringBone remodelingCartilageCell Differentiation processCell SeparationCell TherapyCellsChondrocytesClinicalDataDepositionDevelopmentDiseaseDoctor of PhilosophyEnvironmentEquilibriumExhibitsExtracellular MatrixFemaleFluorescent ProbesFunctional disorderGenesGeneticGenetic EngineeringGrowth FactorHistologicHyperalgesiaHypertrophyImageImmuneImmune responseIn VitroInflammationInflammatoryInjectionsInjuryInterleukin-4JointsKneeKnee jointLabelLuciferasesMacrophageMatrix MetalloproteinasesMeasuresMediatingMesenchymalMethodsModalityModelingMonitorMusMusculoskeletalOrthopedic SurgeryOutcomePainPathologicPathologyPathway interactionsPeptide HydrolasesPhenotypeProcessProductionPropertyProtein AnalysisRandomizedResearchResearch PersonnelSeveritiesSignal TransductionSite-Directed MutagenesisStromal CellsSynovial FluidSynovitisTestingTherapeuticTissuesTraumatic ArthropathyUndifferentiatedadult stem cellanterior cruciate ligament rupturearthropathiesarticular cartilageautocrinecartilage degradationcartilage regenerationcell typechondroprotectionclinically relevantcytokinedisabilityeffective therapyefficacious treatmentengineered stem cellsexperimental studygain of functiongenetically modified cellsimmunoregulationimprovedin vitro Modelin vivoin vivo imaginginflammatory markerinflammatory milieujoint inflammationjoint injurymalemid-career facultymouse modelnext generationnovelparacrinepreventprofessorregenerativeresponserunx proteinsstemstem cellsstructural imagingtissue repairtranscription factortranscriptome sequencingtreatment effect
项目摘要
ABSTRACT
INVESTIGATORS: Rhima Coleman, PhD (PI) is an Associate Professor of Biomedical Engineering focused on
genetic engineering of stem cells for the treatment of joint pathology. Tristan Maerz, PhD (Co-PI) is an Assistant
Professor of Orthopaedic Surgery with expertise in PTOA pathophysiology and synovial inflammation.
RESEARCH CONTEXT: Persistent intra-articular inflammation is a recognized driver of joint pathology during
post-traumatic osteoarthritis (PTOA) progression. Mesenchymal stem/multipotent stromal cells (MSCs) possess
potent anti-inflammatory properties, and MSC-derived chondrocytes (MdChs) have shown promise as a
regenerative intra-articular treatment. Successful implementation of MdChs as a cellular therapy is currently
hindered by rapid hypertrophic maturation of MdChs driven by the transcription factor RUNX2, which is
exacerbated by cytokines known to be enriched in the PTOA joint. We have genetically engineered MdChs to
autonomously suppress RUNX2 (sRX2-MdChs), and, therefore, chondrocyte hypertrophy, which supports
cartilage formation, even under inflammation. Critically, our preliminary data also indicate that the secretome of
these genetically modified cells markedly reduce the local pro-inflammatory environment by inducing
repolarization of pro-inflammatory macrophages (M1) into the anti-inflammatory (M2) phenotype.
OBJECTIVE: To test the disease-modifying and anti-inflammatory efficacy of genetically engineered RUNX2-
suppressing MdChs as a cellular treatment in a murine model of PTOA.
SPECIFIC AIMS: 1). Demonstrate that a single sRX2-MdCh injection blocks pathological inflammation and
PTOA progression following joint injury. 2). Characterize the mechanisms that mediate the autocrine and
paracrine effects of the sRX2-MdChs secretome on cartilage formation and the anti-inflammatory cellular
crosstalk between sRX2-MdChs and macrophages in vitro.
RESEARCH PLAN: In Aim 1, we will employ a noninvasive murine joint injury model of PTOA to test the anti-
inflammatory and PTOA-mitigating effects of a single sRX2-MdCh injection following injury. Male and female
mice will be randomized to 1) sRX2-MdChs; 2) Scramble-MdChs; 3) Unmodified/WT MSCs; or 4) Vehicle. We
will use a multifaceted set of live, in vivo and ex vivo outcomes to assess joint pain, intra-articular inflammation
and protease activity, bone remodeling, and articular cartilage damage to assess PTOA severity. We will track
intra-articular retention of injected cells via live fluorescent monitoring of luciferase activity and a near-infrared
tag. In Aim 2, we will test the hypothesis that the observed autocrine and paracrine effects of the sRX2-MdCh
secretome are mediated by IL-4 and assess the mechanism by which IL-4 effects MdCh cartilage formation and
M1-to-M2 macrophage polarization.
摘要
研究人员:Rhima Coleman,博士(PI),生物医学工程副教授,专注于
干细胞基因工程用于关节病理治疗。特里斯坦·梅尔兹,博士(共同投资),助理
骨科教授,擅长PTOA病理生理学和滑膜炎症。
研究背景:持续的关节内炎症是公认的关节病理的驱动因素
创伤后骨关节炎(PTOA)进展。间充质干细胞/多能基质细胞(MSCs)具有
强大的抗炎特性,以及MSC来源的软骨细胞(MdChs)已显示出作为一种
再生性关节内治疗。作为一种细胞疗法,mdchs的成功实施目前
受转录因子RUNX2驱动的MdChs快速肥大成熟的阻碍,RUNX2是
已知的在PTOA关节中丰富的细胞因子加剧了这种情况。我们通过基因工程改造MdChs来
自主抑制RUNX2(sRX2-MdChs),因此,软骨细胞肥大,这支持
软骨形成,即使在炎症状态下也是如此。关键的是,我们的初步数据还表明,
这些转基因细胞通过诱导局部促炎环境显著减少
促炎症巨噬细胞(M1)复极化为抗炎(M2)表型。
目的:检测基因工程RUNX2-2的抗炎和抗炎作用。
在PTOA小鼠模型中抑制mdchs作为一种细胞治疗。
具体目标:1)。证明一次sRX2-MDCH注射可以阻止病理性炎症和
关节损伤后的PTOA进展。2)。描述调节自分泌和
SRX2-mdChs分泌体对软骨形成和抗炎细胞的旁分泌作用
SRX2-mdCHs与巨噬细胞的体外串扰。
研究计划:在目标1中,我们将采用无创的PTOA小鼠关节损伤模型来测试抗PTOA的作用。
单次注射sRX2-MDCH对损伤后炎症和PTOA的缓解作用。男性和女性
将小鼠随机分为1)sRX2-mdChs组;2)scruble-mdChs组;3)未修饰/WT MSCs组;或4)载体组。我们
将使用一套多方面的活体、体内和体外结果来评估关节疼痛、关节内炎症
并用蛋白水解酶活性、骨重建和关节软骨损伤来评估PTOA的严重程度。我们会追踪
通过实时荧光监测荧光素酶活性和近红外线技术实现注射细胞在关节内的滞留
标签。在目标2中,我们将检验这样一个假设,即观察到的sRX2-MDCH的自分泌和旁分泌效应
分泌组由IL-4介导,并评估IL-4影响MDCH软骨形成和
M_1~M_2巨噬细胞极化。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Rhima Coleman其他文献
Rhima Coleman的其他文献
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{{ truncateString('Rhima Coleman', 18)}}的其他基金
Proteoglycan Regulation of Growth Plate Cartilage Calcification
生长板软骨钙化的蛋白多糖调节
- 批准号:
8037730 - 财政年份:2009
- 资助金额:
$ 19.76万 - 项目类别:
Proteoglycan Regulation of Growth Plate Cartilage Calcification
生长板软骨钙化的蛋白多糖调节
- 批准号:
7800300 - 财政年份:2009
- 资助金额:
$ 19.76万 - 项目类别:
Proteoglycan Regulation of Growth Plate Cartilage Calcification
生长板软骨钙化的蛋白多糖调节
- 批准号:
7674929 - 财政年份:2009
- 资助金额:
$ 19.76万 - 项目类别:
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