BCCMA: Targeting Osteoarthritis Pain and Progression: Proteomics, RNASeq & Immunostaining to elucidate the immune pathotypes of OA
BCCMA:针对骨关节炎疼痛和进展:蛋白质组学、RNASeq
基本信息
- 批准号:10590409
- 负责人:
- 金额:--
- 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:2023-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AgeAnimal ModelAnti-Inflammatory AgentsBiological MarkersCaringCartilageCell LineCellsClinicalClinical DataClinical TrialsComplementComplement ActivationDataData SetDegenerative polyarthritisDevelopmentDiseaseDisease PathwayEarly treatmentEnvironmentEtiologyFibroblastsGene ExpressionGene Expression ProfileGenetic TranscriptionGoalsHealthHealthcare SystemsHeterogeneityHistologicHumanImmuneInflammationInflammatoryInformaticsJointsLaboratoriesMachine LearningMacrophageMechanicsMediatorMilitary PersonnelMolecularMolecular DiseaseMolecular ProfilingMusNerveNerve Growth FactorsOutcomePainPathogenesisPathologyPathway interactionsPharmaceutical PreparationsPhenotypePopulationProteomicsResearchSamplingSerumStem Cell FactorStratificationSynovial FluidSynovial MembraneTestingTherapeuticTissuesTraumatic ArthropathyUnited States National Institutes of HealthVeteransbiomarker developmentboneburden of illnesschronic paincohortcomplement systemcytokinedisabilityhuman tissueimprovedjoint injurymast cellmeniscal tearmilitary veterannew therapeutic targetnovel therapeutic interventionosteoarthritis painpain reductionpre-clinicalpreventradiological imagingresponsesingle-cell RNA sequencingspecific biomarkerssuccesstargeted treatmenttranscriptome sequencingtreatment response
项目摘要
The TOPP Collaborative Merit will test the central hypothesis that heterogeneity in OA pain and structural
progression is related to the “immune pathotype” of OA, which arises from the variability in the cellular and
molecular responses of bone, cartilage, and synovium to inflammation and joint mechanical environment. The
overarching Specific Aims are: Aim 1: To improve understanding of osteoarthritis (OA) pathogenesis to enable
development of targeted early treatment approaches; and Aim 2: To establish preclinical and clinical data for
new therapeutic targets to reduce pain and prevent OA progression.
This VA Merit is Project 2 of our TOPP Collaborative Merit. This Merit will use biospecimens from early and
late OA clinical cohorts prevalent in the the VA health care system to define the immune pathotypes of OA,
with the ultimate goal of using biomarkers for these pathotypes to guide care. Previous studies from our
laboratory implicate “low-grade” innate immune inflammation, and we previously identified key roles for
dysregulated activation of the complement system, mast cells, and inflammatory macrophage in the
pathogenesis of OA. In further invetigations of the cellular, transcriptional and molecular profiles of synovial
membranes from early and late OA, we observe distinct transcriptional signatures, immune cell populations,
and immune pathway activation. We hypothesize that differences in the immune cell composition and
activation states in synovium, bone and cartilage will identify “immune pathotypes” of OA, and that these
immune pathotypes will be associated with differential levels of pain, structural progression, and/or response to
treatment. In Aim 1, we propose to perform proteomic, bulk RNA-Seq, single cell RNA-Seq, and multiplex
immunostaining of human pre-OA (with Dr. Chu) and OA synovial tissues. Aim 2 will perform integrated
informatic analyses using machine learning and other approaches to identify immune pathotypes of human
pre-OA and OA. Aim 3 will determine if the immune pathotypes identified correlate with OA pain and structural
pathology in humans, and/or response to tVNS (with Dr. Humphrey) or anti-NGF (with Dr. Nakamura) in mice.
Success of the herein proposed studies and of our overarching TOPP Collaborative Merit proposal would
transform our understanding of the pathobiology of OA, and could lead to more effective approaches to treat
pain and the first ever disease-modifying therapy for OA.
TOPP协作优点将检验中心假设,即OA疼痛和结构的异质性
进展与OA的“免疫病理型”有关,其起因于细胞和免疫系统的变异性。
骨、软骨和滑膜对炎症和关节机械环境的分子反应。的
总体具体目标是:目标1:提高对骨关节炎(OA)发病机制的认识,使
目标2:建立针对以下疾病的临床前和临床数据:
新的治疗靶点,以减轻疼痛和预防OA进展。
这个VA优点是我们的TOPP合作优点的项目2。本Merit将使用早期和晚期的生物标本,
在VA卫生保健系统中流行的晚期OA临床队列,以定义OA的免疫病理型,
最终目标是使用这些病理类型的生物标志物来指导护理。我们以前的研究
实验室暗示“低度”先天免疫炎症,我们以前确定了关键作用,
补体系统、肥大细胞和炎性巨噬细胞的激活失调,
OA的发病机制。在进一步研究滑膜细胞,转录和分子概况,
从早期和晚期OA的膜,我们观察到不同的转录签名,免疫细胞群,
和免疫途径激活。我们假设,免疫细胞组成的差异和
滑膜、骨和软骨中的激活状态将识别OA的“免疫病理类型”,并且这些免疫病理类型将被识别为OA的“免疫病理类型”。
免疫病理型将与疼痛的不同水平、结构进展和/或对
治疗在目标1中,我们建议进行蛋白质组学、批量RNA-Seq、单细胞RNA-Seq和多重RNA-Seq。
人前OA(与Chu博士一起)和OA滑膜组织的免疫染色。Aim 2将执行集成
使用机器学习和其他方法进行信息学分析以识别人类免疫病理类型
前OA和OA。目的3将确定所鉴定的免疫病理类型是否与OA疼痛和结构相关。
人类的病理学和/或小鼠对tVNS(Humphrey博士)或抗NGF(中村博士)的反应。
本文提出的研究和我们的总体TOPP协作绩效提案的成功将
改变我们对OA病理生物学的理解,并可能导致更有效的治疗方法。
疼痛和首个针对OA的疾病修饰疗法。
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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William H Robinson其他文献
Immune tolerance of citrullinated peptides.
瓜氨酸肽的免疫耐受。
- DOI:
10.1038/s41584-024-01081-0 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
R. Thomas;William H Robinson - 通讯作者:
William H Robinson
Imatinib for the treatment of rheumatic diseases
伊马替尼用于治疗风湿性疾病
- DOI:
10.1038/ncprheum0465 - 发表时间:
2007-04-01 - 期刊:
- 影响因子:32.700
- 作者:
Ricardo T Paniagua;William H Robinson - 通讯作者:
William H Robinson
Human peptidome display
人类肽组展示
- DOI:
10.1038/nbt.1888 - 发表时间:
2011-06-07 - 期刊:
- 影响因子:41.700
- 作者:
William H Robinson;Lawrence Steinman - 通讯作者:
Lawrence Steinman
William H Robinson的其他文献
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{{ truncateString('William H Robinson', 18)}}的其他基金
Investigating the IL-4/13 Axis in Osteoarthritis
研究骨关节炎中的 IL-4/13 轴
- 批准号:
9891690 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Investigating the IL-4/13 Axis in Osteoarthritis
研究骨关节炎中的 IL-4/13 轴
- 批准号:
10092814 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Investigating the IL-4/13 Axis in Osteoarthritis
研究骨关节炎中的 IL-4/13 轴
- 批准号:
10438519 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Investigating the IL-4/13 Axis in Osteoarthritis
研究骨关节炎中的 IL-4/13 轴
- 批准号:
10553629 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Targeting Mast Cells in Post-Traumatic Joint Rehabilitation and Osteoarthritis
在创伤后关节康复和骨关节炎中靶向肥大细胞
- 批准号:
10025268 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Targeting Mast Cells in Post-Traumatic Joint Rehabilitation and Osteoarthritis
在创伤后关节康复和骨关节炎中靶向肥大细胞
- 批准号:
10672163 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Targeting Mast Cells in Post-Traumatic Joint Rehabilitation and Osteoarthritis
在创伤后关节康复和骨关节炎中靶向肥大细胞
- 批准号:
10284924 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Large-Scale Characterization of Anti-Cancer Antibody Responses in Lung Adenocarci
肺腺癌抗癌抗体反应的大规模表征
- 批准号:
8664101 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Large-Scale Sequencing and Characterizing of Autoantibody Responses
自身抗体反应的大规模测序和表征
- 批准号:
8732967 - 财政年份:2014
- 资助金额:
-- - 项目类别:
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