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OA疼痛和结构性疼痛异质性的中心假设