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

• 批准号: 10590409
• 负责人: William H Robinson
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10590409
• 关键词: Age; Animal Model; Anti-Inflammatory Agents; Biological Markers; Caring; Cartilage; Cell Line; Cells; Clinical; Clinical Data; Clinical Trials; Complement; Complement Activation; Data; Data Set; Degenerative polyarthritis; Development; Disease; Disease Pathway; Early treatment; Environment; Etiology; Fibroblasts; Gene Expression; Gene Expression Profile; Genetic Transcription; Goals; Health; Healthcare Systems; Heterogeneity; Histologic; Human; Immune; Inflammation; Inflammatory; Informatics; Joints; Laboratories; Machine Learning; Macrophage; Mechanics; Mediator; Military Personnel; Molecular; Molecular Disease; Molecular Profiling; Mus; Nerve; Nerve Growth Factors; Outcome; Pain; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Proteomics; Research; Sampling; Serum; Stem Cell Factor; Stratification; Synovial Fluid; Synovial Membrane; Testing; Therapeutic; Tissues; Traumatic Arthropathy; United States National Institutes of Health; Veterans; biomarker development; bone; burden of illness; chronic pain; cohort; complement system; cytokine; disability; human tissue; improved; joint injury; mast cell; meniscal tear; military veteran; new therapeutic target; novel therapeutic intervention; osteoarthritis pain; pain reduction; pre-clinical; prevent; radiological imaging; response; single-cell RNA sequencing; specific biomarkers; success; targeted treatment; transcriptome sequencing; treatment response

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。