Translating the Resolution of Inflammation: MC3 in human arthritis synovia

关节炎关节内过度活跃的细胞可能是有害的和破坏性的，导致疼痛和衰弱的疾病，称为类风湿关节炎（RA；影响约1%的西方世界人口）。在过去的二十年里，我们研究了存在于我们体内的生物途径的性质和影响，以解决这些炎症细胞的过度活跃，从而改善疾病的预后。其中一个途径是本项目的重点。到目前为止，我们已经应用了分子（观察基因）和药理学（使用天然和合成分子/化合物）方法来了解这种生物系统-在我们体内自然表达-如何控制和解决炎症：我们现在需要将我们的发现转化为人类病变细胞，并且确实准备好了！我们的初步数据表明，用合成化合物（模拟这种生物途径的天然蛋白质）治疗风湿性关节炎关节的炎症组织和细胞，可以减少导致关节破坏的“坏”分子的产生。这些分子（如肿瘤坏死因子）是“坏的”，因为它们可以通过增强关节白细胞的活性和招募白细胞来使疾病永久化，同时抑制“好”细胞的反应。因此，我们提出了两个主要问题：1)新的生物途径在RA关节中是否活跃？以及它是如何运作的。2)我们能否利用目前可用的合成激素/分子利用生物途径（以及途径中的特定蛋白质）来减少类风湿性关节炎关节内的过度活动，特别是关注关节内的特定和有害细胞？我们将采集关节组织（取自接受膝关节/髋关节置换治疗的患者或超声引导活检的患者），并在模拟自然条件的环境中进行培养。因此，在这些培养中，i)我们将测试我们的合成化合物，以验证在RA关节中起作用的生物途径，以确认这条研究路线对于开发潜在的RA新疗法是可行的；ii)我们将从RA关节中提取细胞，解剖我们的合成疗法所引起的抗炎作用。我们将研究这些破坏性细胞产生的分子的产生。最后，我们将利用一个独特的滑膜组织生物库（通过MRC资助，通过由一位申请人领导的早期关节炎病理生物学联盟[PEAC]收集）来研究该途径（介质/酶/靶标）中与i)疾病阶段和ii)治疗管理相关的元素的潜在调节。我们对项目的完成充满信心，对主要问题的肯定答案将为开发新的抗关节炎疗法铺平道路，这些疗法将利用“炎症的自然解决”概念。我们方法的新颖之处在于利用我们身体自然消炎的基本目标的有效性，将我们的工作转化为人类环境，为因这种使人衰弱的疾病而生活质量差的患者实现临床效益。这个项目产生的结果将为我们目前的努力提供强有力的支持，让学术/工业合作伙伴参与治疗方法的设计和开发，期望这些新治疗方法的副作用比目前治疗方法的副作用要低得多。最后，应该指出的是，基于这一途径的新疗法正在出现（在IIb期进行测试并获得大型制药公司的许可），我们正积极与MRC技术公司合作，利用这一研究路线来开发新的和特定的分子。因此，这一调查性和探索性（主要是学术性）项目将为与药物发现规划有关的平行努力提供信息。

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.