The ACKR2-CCR2 axis in development and disease.

白色血细胞（白细胞）进入组织和在组织内的运动由称为趋化因子的专门蛋白质调节。趋化因子由一系列细胞和组织产生，并与白细胞上称为受体的分子相互作用。因此，例如，当组织发炎或感染时，它会产生趋化因子，然后将白细胞吸引到发炎部位。这些白细胞然后杀死入侵的细菌和病毒，并帮助修复受损的组织。因此，趋化因子是极其重要的生物调节剂。趋化因子及其受体的缺点是，它们也参与将白细胞吸引到以前健康的组织部位，从而引起所谓的自身免疫性和炎症性疾病。例如，在类风湿性关节炎中，白细胞被不适当地吸引到关节，一旦进入关节，它们就不会杀死细菌，而是开始杀死组织，给患者带来严重的问题。因此，趋化因子及其受体是治疗的重要靶点。我们对称为“非典型趋化因子受体”的分子特别感兴趣。这些分子微调趋化因子驱动的反应，并参与组织内白细胞定位的调节。这项拟议的工作计划具体涉及这些非典型趋化因子受体之一，称为ACKR 2。ACKR 2破坏参与炎症的趋化因子，因此它是炎症反应的“负调节因子”。我们已经将其与广泛的人类炎症病理学联系起来，并表明它对炎症反应的解决至关重要。在目前的项目资助中，我们建议使用基础科学和临床重点的方法来更详细地分析ACKR 2的功能。这是非常重要的，因为它将提高我们的理解的整体编排的趋化因子的功能，并将提供新的潜在的治疗targets.Specifically，在这个程序中，我们建议检查新的作用ACKR 2在调节什么是所谓的淋巴系统。这个系统对于从我们的组织中排出液体是必不可少的，也是免疫反应发展不可或缺的贡献者。到目前为止，我们已经产生的数据表明，ACKR 2参与建立淋巴管网络，我们建议对此进行相当详细的研究。我们将定义这背后的生物学机制以及功能和病理学意义。第二，该计划将侧重于我们对ACKR 2参与转移过程的新观察。转移通常是癌症的终末期，并且是转移杀死了绝大多数癌症患者。缺乏ACKR2的小鼠基本上不会发生转移，我们现在建议尝试研究这背后的机制。我们还表明，这些数据突出了ACKR2作为用于治疗人类转移的潜在治疗靶点。因此，我们将产生能够抑制ACKR2功能的化合物，并将在各种转移模型中测试这些化合物。

The movement of white blood cells (leukocytes) into and within tissues is regulated by specialised proteins called chemokines. Chemokines are produced by a range of cells and tissues and interact with molecules called receptors on the leukocytes. Therefore, for example, when a tissue becomes inflamed or infected it produces chemokines which then attract leukocytes to the inflamed sites. These leukocytes then kill invading bacteria and viruses and help to repair the damaged tissue. Chemokines are therefore extremely important biological regulators. The downside of chemokines, and their receptors, is that they are also involved in attracting leukocytes to previously healthy tissue sites to give rise to, what are called, autoimmune and inflammatory diseases. So, for example, in rheumatoid arthritis leukocytes are attracted inappropriately to joints and once there, instead of killing bacteria, they start to kill the tissue and cause profound problems for the patients. Chemokines and their receptors are therefore important targets for therapy.We have a particular interest in molecules called 'atypical chemokine receptors'. These molecules fine-tune chemokine-driven responses and are involved in the regulation of leukocyte positioning within tissues. This proposed Programme of work relates specifically to one of these atypical chemokine receptors which is called ACKR2. ACKR2 destroys the chemokines which are involved in inflammation and it is therefore a 'negative regulator' of inflammatory responses. We have implicated it in a wide range of human inflammatory pathologies and have shown that it is essential for the resolution of the inflammatory response. In the current Programme Grant we propose to use basic scientific, and clinically focused, approaches to try to analyse the functions of ACKR2 in more detail. This is of importance as it will enhance our understanding of the overall orchestration of chemokine function and will provide novel potential therapeutic targets.Specifically, in this Programme, we propose to examine novel roles for ACKR2 in the regulation of what is called the lymphatic system. This system is essential for the drainage of fluid from our tissues and is also an indispensable contributor to the development of immune responses. Data that we have generated so far indicate that ACKR2 is involved in establishing networks of lymphatic vessels and we propose to examine this in considerable detail. We will define the biological mechanisms behind this as well as the functional and pathological implications. Secondly the Programme will focus on new observations that we have made concerning the involvement of ACKR2 in the process of metastasis. Metastasis is frequently the terminal stage of cancer and it is metastasis that kills the vast majority of cancer patients. Mice that lack ACKR2 basically do not develop metastasis and we now propose to try to examine the mechanisms behind this. We also suggest that these data highlight ACKR2 as a potential therapeutic target for use in treating human metastasis. We will therefore generate compounds capable of inhibiting ACKR2 function and will test these in various models of metastasis.