Translating the Resolution of Inflammation: MC3 in human arthritis synovia

转化炎症消退：人类关节炎滑液中的 MC3

• 批准号: MR/K013068/1
• 负责人: Mauro Perretti
• 金额: $ 44.93万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK013068%2F1
• 关键词: Translating; Resolution; Inflammation; MC3; human

Overactive cells within the arthritic joint can be detrimental and destructive leading to the painful and debilitating disease called Rheumatoid Arthritis (RA; affecting ~1% of western world population). For the last twenty years we have studied the nature and impact of biological pathways existing within our bodies to resolve the hyperactivity of these inflamed cells and thus improve disease outcome. One such pathway is the focus of the present project. We have so far applied molecular (observing genes) and pharmacological (using natural and synthetic molecules/compounds) approaches, to understand how this biological system - which is naturally expressed in our body - can control and resolve inflammation: WE NOW NEED TO TRANSLATE OUR FINDINGS TO HUMAN DISEASED CELLS, and indeed are ready! Our preliminary data indicates that treatment of inflamed tissue and cells from the RA joints with synthetic compounds (mimicking the natural proteins of this biological pathway) decreases the generation of 'bad' molecules that cause joint destruction. These molecules (e.g. TNF) being 'bad' in the sense that they can perpetuate the disease by enhancing the activity of and recruiting white blood cells to the joint, as well as dampening the response of the 'good' cells. Thus we ask two main questions:1) Is the novel biological pathway active in RA joints? And how does it operate.2) Can we harness the biological pathway (and specific proteins within the pathway) with currently available synthetic hormones/molecules, to reduce hyperactivity within the RA joint, with particular focus on specific and detrimental cells within the joint?We will take joint tissue (from patients undergoing knee/hip replacement therapy or from ultrasound-guided biopsies) and culture this in an environment which would mimic the natural conditions. Therefore, in these cultures i) we will test our synthetic compounds to validate the biological pathway operative in the RA joint to confirm this line of research is feasible for development of potential new therapeutics for RA; ii) we will extract cells from RA joint to dissect the anti-inflammatory actions evoked by our synthetic therapeutics. We will study the production of molecules that these destructive cells produce.Finally, we will capitalize on a unique biobank of synovial tissue (collected thanks to MRC funding, via the Pathobiology of Early Arthritis Consortium [PEAC], led by one of the applicants) to study potential modulation of elements of this pathway (mediators/enzymes/targets) in relation to i) disease stage and ii) therapeutic management.We are confident completion of the project and, potentially, affirmative answers to the main questions will pave the way to the development of new anti-arthritic therapeutics that will capitalise on the 'natural resolution of inflammation' concept. The novelty of our approach lies in the validity of exploiting targets fundamentally used by our body to naturally resolve inflammation, translating our work into the human settings to achieve clinical benefit for patients that have poor quality of life due to this debilitating disease. The results produced with this project will provide strong support to our current effort to engage academic/industrial collaborators to the design and development of therapies, expecting that these novel therapeutics will be burdened by a much lower degree of side-effects than those observed with current therapies.Finally, it should be noted that new therapeutics depicting on this pathway are now emerging (tested in Phase IIb and licenced to big pharma), and that we are actively engaged with MRC Technology to exploit this line of research for novel and specific molecules. Therefore, this investigative and exploratory (essentially academic) project will inform parallel efforts in relation to drug discovery programmes.

关节炎中过度活跃的细胞可能是有害和破坏性的，导致痛苦和令人衰弱的疾病称为类风湿关节炎（RA；影响西方世界人口的约1％）。在过去的二十年中，我们研究了体内存在的生物途径的性质和影响，以解决这些发炎细胞的多动症，从而改善疾病的预后。这样的途径是本项目的重点。到目前为止，我们已经采用了分子（观察基因）和药理学（使用天然和合成分子/化合物）方法，以了解该生物系统如何自然表达在我们体内 - 我们现在需要控制和解决炎症：我们现在需要将我们的发现转化为人类疾病细胞，并确实准备好了！我们的初步数据表明，用合成化合物（模仿该生物学途径的自然蛋白质）对RA关节的发炎组织和细胞进行处理会降低导致关节破坏的“坏”分子的产生。这些分子（例如TNF）是“不良”的意义，即它们可以通过增强和募集白细胞的活性并抑制“好”细胞的反应来使疾病永久化。因此，我们提出了两个主要问题：1）新型生物学途径是否在RA关节中活跃？ 2）我们可以使用当前可用的合成激素/分子来利用生物学途径（以及途径中的特定蛋白质），以减少RA关节内的多动症，特别关注关节内的特定和有害的细胞？我们将采取关节组织（从正在进行的膝盖/hip替代治疗中，从经过的膝盖/hip替代疗法中进行了这种环境和自然的态度），并且在超级自然的情况下进行了这种态度和文化。因此，在这些培养物中i）我们将测试我们的合成化合物，以验证RA关节中的生物途径可操作剂以确认这一研究对于开发RA的潜在新疗法是可行的。 ii）我们将从RA关节中提取细胞，以剖析我们的合成疗法引起的抗炎作用。 We will study the production of molecules that these destructive cells produce.Finally, we will capitalize on a unique biobank of synovial tissue (collected thanks to MRC funding, via the Pathobiology of Early Arthritis Consortium [PEAC], led by one of the applicants) to study potential modulation of elements of this pathway (mediators/enzymes/targets) in relation to i) disease stage and ii) therapeutic管理层我们有信心完成该项目，并且可能对主要问题的肯定答案将为开发新的抗关节疗法的发展铺平道路，这些抗性疗法将利用“自然解决炎症”概念。我们方法的新颖性在于利用身体从根本上使用的目标自然解决炎症的有效性，将我们的工作转化为人类环境，以便为由于这种令人衰弱的疾病而具有较差生活质量的患者获得临床益处。该项目产生的结果将为我们目前的努力提供强大的支持，以使学术/工业合作者参与疗法的设计和开发，并期望这些新颖的治疗学将受到比当前疗法观察到的副作用的负担要低得多，而与当前的治疗相比，应从当前的治疗中观察到的。积极参与MRC技术，以利用这种研究线来为新颖的分子和特定分子。因此，这个调查性和探索性（本质上是学术）项目将为与药物发现计划有关的并行努力提供依据。

项目成果

Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis

• DOI: 10.1038/s41467-020-14421-x
• 发表时间: 2020-02-06
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Montero-Melendez, Trinidad;Nagano, Ai;Perretti, Mauro
• 通讯作者: Perretti, Mauro

Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis.

• DOI: 10.1126/scitranslmed.aac5608
• 发表时间: 2015-11-25
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Headland SE;Jones HR;Norling LV;Kim A;Souza PR;Corsiero E;Gil CD;Nerviani A;Dell'Accio F;Pitzalis C;Oliani SM;Jan LY;Perretti M
• 通讯作者: Perretti M

Melanocortin agonism as a viable strategy to control alveolar bone loss induced by oral infection.

黑皮质素激动是控制口腔感染引起的牙槽骨丢失的可行策略。

• DOI: 10.1096/fj.201600790r
• 发表时间: 2016
• 期刊: official publication of the Federation of American Societies for Experimental Biology
• 作者: Madeira MF

Association between periodontal disease and inflammatory arthritis reveals modulatory functions by melanocortin receptor type 3.

牙周病和炎症性关节炎之间的关联揭示了 3 型黑皮质素受体的调节功能。

• DOI: 10.1016/j.ajpath.2014.04.009
• 发表时间: 2014
• 期刊: The American journal of pathology
• 作者: Montero-Melendez T

Video abstract: Atlas of Inflammation Resolution. Overview.

视频摘要：炎症消解图集。

• DOI: 10.57722/heel.figshare.23898780
• 发表时间: 2023
• 作者: Gupta S