Activation of endogenous progenitors via a nanoparticle-conjugated fibrous system to enhance meniscus repair
通过纳米颗粒共轭纤维系统激活内源祖细胞以增强半月板修复
基本信息
- 批准号:10607306
- 负责人:
- 金额:$ 47.42万
- 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:2023-02-20 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAccelerationAdultAffectAftercareAgeAgingAnimal ModelAnteriorAntibodiesAttenuatedBiologicalBiologyCartilageCell LineageCell physiologyCellsChemistryClinical TreatmentDataDegenerative polyarthritisDevelopmentDiseaseDoseDrug Delivery SystemsErinaceidaeExcisionFamily suidaeFemurFibrocartilagesGoalsHealthHeterogeneityHomeostasisHornsHumanInjuryIntra-Articular InjectionsJointsKneeKnee InjuriesKnee OsteoarthritisKnowledgeLabelLubricantsLubricationMaintenanceMechanicsMediatingMeniscus structure of jointMesenchymal Stem CellsMetabolismMiniature SwineModelingMusNanotechnologyNatural regenerationOlder PopulationOligonucleotidesOperative Surgical ProceduresOrganPain managementPathway interactionsPatientsPatternPharmaceutical PreparationsPharmacotherapyPlayProceduresProcessProliferatingReporterRoleShockSignal PathwaySignal TransductionSiteStructureSurgical ManagementSurgical suturesSystemTestingTherapeuticThickTissuesTranslatingWorkabsorptionagedaging populationcell motilitydesignfabricationgain of functionhealingimprovedin vivoinnovationloss of functionmeniscal tearmeniscus injurymigrationmouse modelmultidisciplinarynanoparticlenanoparticle deliverynovelnovel therapeutic interventionnovel therapeuticspalliativepreservationpreventprogenitorpurmorphaminerecruitrepair functionrepairedresponseresponse to injuryscaffoldsingle-cell RNA sequencingsmoothened signaling pathwayspatiotemporalstemstem cellssystemic barriertherapeutic targettibiatool
项目摘要
Project Summary
Meniscus
Meniscus
initiation.
therapy
basic
novel
Previous
located
maintain Using a
Gli1-CreER driven Hh reporter mouse line, we recently found that Gli1-labeled cells contribute to the
development of the meniscus horns from 2 weeks of age. In adult and aged mice, Gli1+ cells were localized to
the superficial layer of anterior and posterior meniscal horns, and gradually decreased in number during aging.
In vivo, these cells co-expressed known markers of mesenchymal progenitors as well as the lubricant Prg4. In
culture, meniscal Gli1+ cells possessed high progenitor activities, such as proliferation, migration, and
differentiation, under the control of Hh signal. Using an in vivo mouse meniscus injury model, we showed a
rapid expansion of Gli1-lineage cells at the injury site of anterior horn. Ablation of these Gli1+ cells prior to
injury slowed the meniscus repair process. Strikingly, intra-articular injection of the Hh activator,
Purmorphamine (Pur), following injury accelerated meniscus repair and attenuated OA progression. Based on
these data, we hypothesize that the Hh/Gli1 pathway can be therapeutically targeted to treat meniscus injury
tears are the most common injury to the knee, affecting both young and old populations.
healing is limited, however, and loss of function leads o cartilage loss and osteoarthritis OA)
Current clinical treatment is palliative, and does not restore function, and no disease modifying drug
is available for the t reatment of meniscus injury. Thus, there is a critical need to better understand the
biologic mechanisms and pathways regulating meniscus homeostasis and repair in order to develop
therapeutics. Mesenchymal progenitors play a critical role in tissue maintenance and regeneration.
studies have demonstrated the existence of mesenchymal progenitors in the meniscus, with most
within the superficial layer. Hedgehog (Hh) signaling is one of a few fundamental pathways that
adult stem and progenitor cells in various organs and can activate these cells post injury.
t (
and prevent OA development via the mobilization of endogenous meniscus progenitors.
work
design
Aims
evaluate
scaffold-mediated
The objectives of this
are to understand the role of this novel signaling pathway in meniscus homeostasis and repair and to
a novel drug delivery system to enhance meniscus repair by locally targeting t his pathway. Our specific
are to: 1) determine the function of Hh signaling in meniscus development and repair; 2) synthesize and
a nanoparticle (NP)-conjugated fibrous delivery system for meniscus repair; 3) Assess Pur-NP
repair in a large animal model of meniscus injury.Small (mouse) and large (minipig) animal
models, and complementary experimental tools will be utilized to develop and translate this new therapy.
multidisciplinary
successful, this work will
healing
Our
team has worked together to generate the exciting preliminary data supporting this proposal.
provide a novel therapeutic scaffold that mobilizes meniscus progenitors to improve
of tears that are otherwise considered irreparable.
If
项目摘要
半月板
半月板
入会仪式
治疗
基本
小说
先前
位于
维护使用
Gli 1-CreER驱动的Hh报告基因小鼠系,我们最近发现Gli 1标记的细胞有助于
半月板角从2周龄开始发育。在成年和老年小鼠中,Gli 1+细胞定位于
前、后翼角浅层的数量随年龄增长而逐渐减少。
在体内,这些细胞共表达间充质祖细胞的已知标志物以及润滑剂Prg 4。在
体外培养的胶质细胞Gli 1+细胞具有较高的祖细胞活性,如增殖、迁移和增殖能力,
分化,在Hh信号的控制下。使用体内小鼠半月板损伤模型,我们显示了
Gli 1系细胞在前角损伤部位迅速扩增。这些Gli 1+细胞的消融,
损伤延缓了半月板修复过程。引人注目的是,关节内注射Hh激活剂,
损伤后,Purmorphamine(Pur)加速半月板修复并减弱OA进展。基于
根据这些数据,我们假设Hh/Gli 1通路可以作为治疗半月板损伤的靶点
撕裂是膝盖最常见的损伤,影响年轻人和老年人。
然而,愈合是有限的,并且功能丧失导致软骨丧失和骨关节炎。
目前的临床治疗是姑息性的,不能恢复功能,也没有疾病改善药物
可用于半月板损伤的治疗。因此,迫切需要更好地了解
调节半月板稳态和修复的生物机制和途径,
治疗学间充质祖细胞在组织维持和再生中起关键作用。
研究已经证明半月板中存在间充质祖细胞,其中大多数
在表层内。Hedgehog(Hh)信号传导是少数几个基本途径之一,
成体干细胞和祖细胞在各种器官中,并且可以在损伤后激活这些细胞。
试验),测试
并通过动员内源性半月板祖细胞防止OA发展。
工作
设计
旨在
评价
支架介导
这一目标
是为了了解这种新的信号通路在半月板稳态和修复中的作用,
一种通过局部靶向该途径来增强半月板修复的新型药物递送系统。我们的具体
目的是:1)确定Hh信号传导在半月板发育和修复中的功能; 2)合成和
用于半月板修复的纳米颗粒(NP)缀合的纤维递送系统; 3)评估Pur-NP
半月板损伤大型动物模型的修复。小型(小鼠)和大型(小型猪)动物
模型和补充实验工具将用于开发和转化这种新疗法。
多学科
如果成功,这项工作将
愈合
我们
团队共同努力,产生了令人兴奋的初步数据,支持这一建议。
提供了一种新的治疗支架,
被认为是无法挽回的眼泪
如果
项目成果
期刊论文数量(0)
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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Robert L Mauck其他文献
Robert L Mauck的其他文献
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{{ truncateString('Robert L Mauck', 18)}}的其他基金
Knee Joint Resurfacing with Anatomic Tissue Engineered Osteochondral Implants
使用解剖组织工程骨软骨植入物进行膝关节表面置换
- 批准号:
10704534 - 财政年份:2020
- 资助金额:
$ 47.42万 - 项目类别:
Knee Joint Resurfacing with Anatomic Tissue Engineered Osteochondral Implants
使用解剖组织工程骨软骨植入物进行膝关节表面置换
- 批准号:
10248368 - 财政年份:2020
- 资助金额:
$ 47.42万 - 项目类别:
Hydrogel Delivery of Extracellular Vesicles to Treat Osteoarthritis
水凝胶递送细胞外囊泡治疗骨关节炎
- 批准号:
10631851 - 财政年份:2020
- 资助金额:
$ 47.42万 - 项目类别:
Hydrogel Delivery of Extracellular Vesicles to Treat Osteoarthritis
水凝胶递送细胞外囊泡治疗骨关节炎
- 批准号:
10176189 - 财政年份:2020
- 资助金额:
$ 47.42万 - 项目类别:
Knee Joint Resurfacing with Anatomic Tissue Engineered Osteochondral Implants
使用解剖组织工程骨软骨植入物进行膝关节表面置换
- 批准号:
10454898 - 财政年份:2020
- 资助金额:
$ 47.42万 - 项目类别:
Mechanobiology of Progenitor Cells in Heterotopic Ossification
异位骨化中祖细胞的力学生物学
- 批准号:
10401824 - 财政年份:2018
- 资助金额:
$ 47.42万 - 项目类别:
Mechanobiology of Progenitor Cells in Heterotopic Ossification
异位骨化中祖细胞的力学生物学
- 批准号:
9926811 - 财政年份:2018
- 资助金额:
$ 47.42万 - 项目类别:
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