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 协作奖将测试中心假设，即 OA 疼痛和结构性疼痛的异质性 OA 的进展与 OA 的“免疫病理型”有关，这种病理型是由细胞和细胞的变异性引起的。 骨、软骨和滑膜对炎症和关节机械环境的分子反应。这 总体具体目标是： 目标 1：提高对骨关节炎 (OA) 发病机制的了解，以实现 制定有针对性的早期治疗方法；目标 2：建立临床前和临床数据 减轻疼痛和预防 OA 进展的新治疗目标。 该 VA 优点是我们 TOPP 合作优点的项目 2。该优点将使用早期和 VA 医疗保健系统中流行的晚期 OA 临床队列来定义 OA 的免疫病理类型， 最终目标是使用这些致病型的生物标志物来指导护理。我们之前的研究 实验室暗示“低度”先天免疫炎症，我们之前确定了 补体系统、肥大细胞和炎症巨噬细胞的激活失调 OA 的发病机制。在对滑膜的细胞、转录和分子谱的进一步研究中 从早期和晚期 OA 的膜中，我们观察到不同的转录特征、免疫细胞群、 和免疫途径激活。我们假设免疫细胞组成和 滑膜、骨和软骨的激活状态将识别 OA 的“免疫病理型”，并且这些 免疫病理型与不同程度的疼痛、结构进展和/或对药物的反应有关 治疗。在目标 1 中，我们建议进行蛋白质组学、批量 RNA 测序、单细胞 RNA 测序和多重测序 人类前 OA（与 Chu 博士合作）和 OA 滑膜组织的免疫染色。目标2将执行综合 使用机器学习和其他方法进行信息分析来识别人类的免疫致病型 预 OA 和 OA。目标 3 将确定确定的免疫病理类型是否与 OA 疼痛和结构性相关 人类病理学和/或小鼠对 tVNS（与 Humphrey 博士）或抗 NGF（与 Nakamura 博士）的反应。 本文提出的研究和我们总体 TOPP 合作优点提案的成功将 改变我们对 OA 病理学的理解，并可能带来更有效的治疗方法 疼痛和有史以来第一个针对 OA 的疾病缓解疗法。