Mapping the joint-nerve interactome of the knee
绘制膝关节的关节神经相互作用组图
基本信息
- 批准号:10607479
- 负责人:
- 金额:$ 663.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-23 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAfferent NeuronsAgeAgingAnalgesicsAnatomic ModelsAnatomyArthralgiaAtlasesBiologyC FiberC57BL/6 MouseCell CommunicationCellsCellular Indexing of Transcriptomes and Epitopes by SequencingCommunicationCommunitiesDataData SetDatabasesDegenerative polyarthritisDevelopmentDiseaseElementsEnvironmentEventExhibitsFatty acid glycerol estersGene Expression ProfileGenesGenetic TranscriptionHealthHistologyHistopathologyHumanHyperplasiaImaging TechniquesJointsKneeKnee OsteoarthritisKnee jointLabelLaboratoriesLeadLigandsMapsMedialMediator of activation proteinMeniscus structure of jointMicroscopyMolecularMorphologyMusNerveNeuronal PlasticityNeuronsNeurosciencesNociceptorsOperative Surgical ProceduresPainParvalbuminsPathologicPathologyPatientsPatternProcessPropertyProprioceptorReporterReportingResolutionResourcesSamplingScanningSensoryStandardizationSynovial CellSynovial MembraneSynovitisTestingTherapeuticTimeTissuesbasedifferential expressionholistic approachhuman diseaseimprovedjoint injuryknee painknee replacement arthroplastymolecular phenotypemouse modelmultidisciplinarynerve supplynew therapeutic targetnovelnovel therapeuticsosteoarthritis painosteochondral tissueprogramsquadriceps musclereceptorsexsingle-cell RNA sequencingthree-dimensional modelingtranscriptome sequencingtranscriptomicstranslational scientist
项目摘要
Project Summary
Our multidisciplinary team assembles basic and translational researchers with expertise in joint biology and
neuroscience, proposing a holistic approach to mapping the sensory innervation of murine and human knee
joints. We will use state-of-the-art imaging techniques, combined with transcriptomics to construct 3D models of
the sensory innervation of the knee, compose a cell atlas in which knee afferents are transcriptionally profiled at
a single cell resolution, and document the nerve-joint cell interactome at the transcriptional level. Our overarching
objective is to precisely describe the sensory innervation of the knee, and the dynamic changes occurring with
aging, joint injury, and osteoarthritis (OA). This will provide the Consortium with a rich anatomical and molecular
resource to study mechanisms underlying joint pain and guide the development of novel analgesic strategies.
Aim 1. Documenting the sensory innervation of the healthy and diseased mouse knee: Anatomical and molecular
perspectives. Using fluorescent reporter mice to label nociceptors, C-fiber subsets, and proprioceptors, we will
map the anatomical innervation of the mouse knee in (a) naïve mice of different ages; (b) after joint injury; (c) in
surgically induced OA. We will use ribbon scanning confocal and clearing-enabled lightsheet microscopy to
construct high-resolution 3-D anatomical models of joint innervation. We will backlabel knee-innervating afferents
and use spatial transcriptomics to describe their molecular phenotypes compared to other non-knee innervating
DRG neurons. Aim 2. Documenting the sensory innervation of the healthy and diseased human knee: Anatomical
and molecular perspectives. We will use a unique set of post mortem knee/DRG samples from (1) healthy knees,
age 20-40 (n=15/sex); (2) knees from donors over 70 (n=15/sex), in which we anticipate 80-90% to exhibit OA
pathology. Knee tissues will be collected in a standardized fashion, including synovium, osteochondral plugs
(medial tibial plateau), meniscus, ACL, fat pad, and quadriceps muscle. In each tissue, we will perform (1)
histopathology; (2) IHC for sensory innervation; (3) bulk and scRNAseq; (4) spatial transcriptomics. Matched
DRGs will be used for bulk RNAseq to identify differentially expressed genes (DEG) between the groups provide
information for ligand-receptor analysis. Aim 3. Identifying mediators in the knee synovium that drive disease-
associated neuroplasticity. (1) We will reconstruct the cellular interactome between synovial cells and DRG
neurons in mouse models of aging, joint injury, and OA using scRNAseq of matched synovium and DRG
samples. (2) We will compare patient reports of OA knee pain at the time of TKR to matched synovial histology,
including extent of lining hyperplasia, single-cell transcriptional changes, and innervation. Overall, this project
will provide the community with comprehensive databases of the neuro-articular environment, which can be
mined to (1) undertake mechanistic studies to inhibit pathological neuroplasticity and (2) identify and test new
druggable targets. This strategy will pave the way for the development of novel, targeted, non-addictive, and
safe analgesic therapeutics for the treatment of joint pain.
项目总结
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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Martin K Lotz其他文献
New approach to testing treatments for osteoarthritis: FastOA
骨关节炎治疗测试新方法:快速骨关节炎评估法
- DOI:
10.1136/ard-2023-224675 - 发表时间:
2024-03-01 - 期刊:
- 影响因子:20.600
- 作者:
David Felson;Martin K Lotz;Yuxuan Jin;Morgan Jones;Jason S Kim;Kurt Spindler - 通讯作者:
Kurt Spindler
Martin K Lotz的其他文献
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{{ truncateString('Martin K Lotz', 18)}}的其他基金
Mapping the joint-nerve interactome of the knee
绘制膝关节的关节神经相互作用组图
- 批准号:
10861323 - 财政年份:2023
- 资助金额:
$ 663.31万 - 项目类别:
High resolution 3D mapping of cellular heterogeneity within multiple types of mineralized tissues
多种矿化组织内细胞异质性的高分辨率 3D 绘图
- 批准号:
10705190 - 财政年份:2020
- 资助金额:
$ 663.31万 - 项目类别:
High resolution 3D mapping of cellular heterogeneity within multiple types of mineralized tissues
多种矿化组织内细胞异质性的高分辨率 3D 绘图
- 批准号:
10267740 - 财政年份:2020
- 资助金额:
$ 663.31万 - 项目类别:
High resolution 3D mapping of cellular heterogeneity within multiple types of mineralized tissues
多种矿化组织内细胞异质性的高分辨率 3D 绘图
- 批准号:
10700252 - 财政年份:2020
- 资助金额:
$ 663.31万 - 项目类别:
High resolution 3D mapping of cellular heterogeneity within multiple types of mineralized tissues
多种矿化组织内细胞异质性的高分辨率 3D 绘图
- 批准号:
10816791 - 财政年份:2020
- 资助金额:
$ 663.31万 - 项目类别:
FOXO transcription factors as critical regulators of intervertebral disc aging
FOXO转录因子作为椎间盘老化的关键调节因子
- 批准号:
10617735 - 财政年份:2019
- 资助金额:
$ 663.31万 - 项目类别:
FOXO transcription factors as critical regulators of intervertebral disc aging
FOXO转录因子作为椎间盘老化的关键调节因子
- 批准号:
10399475 - 财政年份:2019
- 资助金额:
$ 663.31万 - 项目类别:
FoxO transcription factors in joint aging and osteoarthritis pathogenesis
FoxO转录因子在关节衰老和骨关节炎发病机制中的作用
- 批准号:
10399471 - 财政年份:2018
- 资助金额:
$ 663.31万 - 项目类别:
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$ 663.31万 - 项目类别:
FoxO transcription factors in joint aging and osteoarthritis pathogenesis
FoxO转录因子在关节衰老和骨关节炎发病机制中的作用
- 批准号:
9916681 - 财政年份:2018
- 资助金额:
$ 663.31万 - 项目类别:
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