Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
基本信息
- 批准号:10613582
- 负责人:
- 金额:$ 43.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-15 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AnisotropyArchitectureAutomobile DrivingBurn injuryCell LineageCellsChemicalsClinicalCollagenCollagen ReceptorsCollagen Type ICommunicationCre lox recombination systemDataData SetDevicesDiseaseElementsExposure toExtracellular MatrixFocal Adhesion Kinase 1Gene Expression ProfileGeneticGenetic TranscriptionHeterotopic OssificationHumanImmobilizationIn VitroInjuryInterventionJointsLabelLesionLigandsLimb structureLinkMechanical StressMesenchymal Stem CellsModelingMolecularMusOsteogenesisPTK2 genePathologicPathway interactionsPatientsPeriodicityPhasePhysical therapyPhysiologic OssificationProcessProtein Tyrosine KinaseProtocols documentationRadialRegulationRoleSeriesSignal TransductionSiteSkeletal boneStretchingSystemTherapeuticTherapeutic InterventionTraumatic injuryWorkcell fate specificationclinical translationclinically relevantcombatdiscoidin domain receptor 2discoidin receptorfibulahip replacement arthroplastyin vivoin vivo Modelinducible Creinhibitor therapyinsightjoint mobilizationlipid biosynthesismechanotransductionmouse modelmusculoskeletal injurynovelosteochondral tissuepreventprogenitorprogramssingle-cell RNA sequencingtargeted treatmenttibiaulna
项目摘要
Project Summary
Heterotopic ossification (HO) is the pathologic formation of extra-skeletal bone forming almost exclusively at
sites of mechanical stress, that occurs in ~20% of patients after hip arthroplasty, burns or musculoskeletal injury.
Currently, no therapeutics or physical therapy-based protocols exist to prevent HO. In this regard, there is a void
in our understanding of the causative mechanotransductive pathways behind this debilitating process. Our
unbiased transcription profiles in mouse HO-mesenchymal progenitor cells (MPCs) recovered from HO sites in
combination with immunostaining of mouse and human HO revealed that a series of mechanotranduction-linked
pathways, including discoidin receptor 2 (DDR2), FAK and the Hippo effectors, YAP and TAZ, are highly
upregulated in tandem with observed changes in extracellular matrix (ECM) alignment. Using a novel, regional
MPC-specific inducible Cre system (Hoxa11-CreERT2), we have compiled preliminary data that support critical
roles for DDR2 signaling and stage-specific immobilization in both triggering FAK/YAP/TAZ signaling and MPC
lineage commitment, but also an unexpected function in controlling ECM alignment. Together, these
observations have led to our central hypothesis that MPC DDR2 signaling is necessary for mobility-induced
changes in ECM alignment that trigger aberrant osteochondral differentiation at HO sites and can be blocked by
DDR2 inhibition or injury stage-specific immobilization.
Aim 1: Define the role of DDR2 as a critical upstream regulator of FAK/YAP/TAZ signaling in controlling
the induction and progression of HO. We hypothesize that DDR2-mechanotransductive signaling alters
osteochondral differentiation and HO in vivo and can be targeted with cell specific deletion models or translatable
clinical therapies.
Aim 2: Determine the optimal post-injury timing during which MPCs can be redirected away from
aberrant osteochondral fate and pathologic ECM alignment through immobilization-based intervention.
We hypothesize that immobilization during the early proliferative phase after injury will block pathologic changes
in ECM alignment with disease-ameliorating effects on MPC fate determination and aberrant ossification.
Aim 3: Characterize the role of mobilization-induced DDR2 activation on collagen alignment/anisotropy
and mechanotransductive signaling. We hypothesize that DDR2 activity drives ECM alignment independently
of limb mobility in vivo or cyclic stretch in vitro.
Impact: The proposed studies will provide a comprehensive and mechanistic understanding of how DDR2 and
joint mobility regulate ECM alignment, cell fate and HO using conditional deletion models and clinical therapies.
项目摘要
异位骨化(HO)是一种几乎完全在骨外形成的病理性骨形成,
机械应力部位,约20%的髋关节置换术、烧伤或肌肉骨骼损伤后患者发生。
目前,没有治疗或物理治疗为基础的协议存在,以防止HO。在这方面,
在我们理解这个衰弱过程背后的致病性机械传导途径。我们
无偏转录谱在小鼠HO-间充质祖细胞(MPC)回收从HO位点,
结合小鼠和人HO的免疫染色显示,
包括盘状蛋白受体2(DDR2)、FAK和Hippo效应子雅普和TAZ在内的多种途径,
与观察到的细胞外基质(ECM)排列的变化串联上调。使用一种新颖的,
MPC特异性诱导Cre系统(Hoxa 11-CreERT 2),我们已经汇编了初步数据,支持关键的
DDR2信号传导和阶段特异性固定在触发FAK/雅普/TAZ信号传导和MPC中的作用
谱系定型,而且在控制ECM对齐中具有意想不到的功能。所有这些
观察结果导致我们的中心假设,即MPC DDR2信号传导对于迁移诱导的
ECM排列的变化触发HO位点的异常骨软骨细胞分化,并可通过
DDR2抑制或损伤阶段特异性固定。
目的1:确定DDR2作为FAK/雅普/TAZ信号传导的关键上游调节因子在控制细胞凋亡中的作用。
HO的诱导和进展。我们假设DDR2-机械转导信号改变了
本发明的目的是在体内检测骨软骨细胞分化和HO的表达,并且可以用细胞特异性缺失模型或可翻译的缺失模型靶向。
临床治疗。
目标2:确定最佳的伤后时机,在此期间,MPC可以被重定向远离
通过基于固定的干预,异常的骨软骨细胞命运和病理性ECM对齐。
我们假设在损伤后的早期增殖期制动将阻断病理变化
ECM与MPC命运决定和异常骨化的疾病改善作用一致。
目的3:表征动员诱导的DDR2活化对胶原排列/各向异性的作用
和机械传导信号。我们假设DDR2活性独立驱动ECM对齐
在体内的肢体活动性或在体外的周期性拉伸。
影响:拟议的研究将提供对DDR2和
使用条件性缺失模型和临床治疗,关节活动性调节ECM排列、细胞命运和HO。
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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Benjamin Levi其他文献
Benjamin Levi的其他文献
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{{ truncateString('Benjamin Levi', 18)}}的其他基金
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification - diversity supplement
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响 - 多样性补充
- 批准号:
10533903 - 财政年份:2021
- 资助金额:
$ 43.34万 - 项目类别:
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
- 批准号:
10832255 - 财政年份:2021
- 资助金额:
$ 43.34万 - 项目类别:
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
- 批准号:
10297550 - 财政年份:2021
- 资助金额:
$ 43.34万 - 项目类别:
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
- 批准号:
10448303 - 财政年份:2021
- 资助金额:
$ 43.34万 - 项目类别:
Neutrophil Biomarker and neutrophil targeted therapy to predict and prevent heterotopic ossification
中性粒细胞生物标志物和中性粒细胞靶向治疗可预测和预防异位骨化
- 批准号:
10900159 - 财政年份:2020
- 资助金额:
$ 43.34万 - 项目类别:
Neutrophil Biomarker and neutrophil targeted therapy to predict and prevent heterotopic ossification
中性粒细胞生物标志物和中性粒细胞靶向治疗可预测和预防异位骨化
- 批准号:
10267729 - 财政年份:2020
- 资助金额:
$ 43.34万 - 项目类别:
Neutrophil Biomarker and neutrophil targeted therapy to predict and prevent heterotopic ossification
中性粒细胞生物标志物和中性粒细胞靶向治疗可预测和预防异位骨化
- 批准号:
10081442 - 财政年份:2020
- 资助金额:
$ 43.34万 - 项目类别:
Targeting Molecular and Cellular Mediators of Inflammation to Prevent Pathologic Cell Differentiation and Heterotopic Ossification
靶向炎症的分子和细胞介质以防止病理性细胞分化和异位骨化
- 批准号:
9906177 - 财政年份:2017
- 资助金额:
$ 43.34万 - 项目类别:
Targeting Molecular and Cellular Mediators of Inflammation to Prevent Pathologic Cell Differentiation and Heterotopic Ossific
靶向炎症的分子和细胞介质以防止病理性细胞分化和异位骨化
- 批准号:
10283122 - 财政年份:2017
- 资助金额:
$ 43.34万 - 项目类别:
Developing New Diagnostic and Timed, TAK1 Specific Treatment Strategies for Trauma Induced Heterotopic Ossification
为创伤引起的异位骨化开发新的诊断和定时 TAK1 特异性治疗策略
- 批准号:
9398623 - 财政年份:2017
- 资助金额:
$ 43.34万 - 项目类别:
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