BCCMA: Targeting Osteoarthritis Pain and Progression: Proteomics, RNASeq & Immunostaining to elucidate the immune pathotypes of OA

TOPP Collaborative Merit将检验以下中心假设：骨性关节炎疼痛和结构性的异质性 进展与骨性关节炎的“免疫病程类型”有关，这种病程类型源于细胞和细胞内的可变性。 骨、软骨和滑膜对炎症和关节机械环境的分子反应。这个 主要的具体目标是：目标1：提高对骨关节炎(OA)发病机制的认识，使 开发有针对性的早期治疗方法；和目标2：建立临床前和临床数据 新的治疗目标，以减轻疼痛和防止骨性关节炎进展。 此VA奖励是我们TOPP协作奖励的项目2。这一优点将使用来自早期和 在退伍军人保健系统中流行的晚期骨性关节炎临床队列，以确定骨性关节炎的免疫病理类型， 最终目标是使用这些致病类型的生物标记物来指导护理。我们之前的研究 实验室牵涉到“低级别”的先天性免疫炎症，我们先前确定了 补体系统、肥大细胞和炎性巨噬细胞的异常激活 骨性关节炎的发病机制。在进一步研究滑膜的细胞、转录和分子图谱中 早期和晚期骨性关节炎的细胞膜，我们观察到不同的转录信号，免疫细胞群， 和免疫途径的激活。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骨性关节炎的“免疫病理类型”，这些 免疫病理类型将与不同程度的疼痛、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、整体RNA-Seq、单细胞RNA-Seq和多重 人前骨性关节炎(与朱医生)和骨性关节炎滑膜组织的免疫染色。AIM 2将执行集成 利用机器学习和其他方法进行信息分析以识别人类免疫病毒型 办公自动化前期和办公自动化。目标3将确定已识别的免疫病理类型是否与骨性关节炎疼痛和结构性相关 人类的病理，和/或对tVNS(与Humphrey博士)或抗NGF(与Nakamura博士)在小鼠的反应。 本文提议的研究和我们总体TOPP协作优点提议的成功将 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 疼痛和有史以来第一个针对骨性关节炎的疾病修正疗法。

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.