C-reactive protein (CRP) as a pathological factor in inflammation and ischemia/reperfusion injury: therapeutic implications

C-反应蛋白（CRP）是一种高度保守的五聚体蛋白，是原型急性期蛋白。近年来，它不仅被确定为炎症反应的标志物，而且也是炎症反应的致病因子。我们先前可以在体外和体内证明，在发炎组织中，局部细胞损伤和膜变化导致循环五聚体CRP（pCRP）解离成其单体亚基（单体=mCRP）。产生的mCRP沉积在炎症区域，并导致现有炎症反应的局部加重。CRP作为局部激活的促炎系统的鉴定导致我们开发新的抗炎治疗策略。这些是通过用1，6-双-（磷酸胆碱）-己烷（CRP配体磷酸胆碱的化学修饰衍生物）稳定CRP来靶向从pCRP到mCRP的解离过程。在我们之前的体内概念验证研究中，我们可以证明这种治疗概念的抗炎潜力。在这个项目中，我们将分析mCRP调节炎症的分子机制。通过CRP的定点诱变，我们将鉴定CRP一级结构内的促炎序列和所述CRP在炎症中的相互作用伴侣的相关结合位点的作用。这将使我们能够更好地理解潜在的分子机制，从而能够识别新的治疗方法，并改进我们现有的治疗药物。在我们以前的工作中鉴定了一种新的病理性促炎机制和治疗靶向CRP的有效性的概念验证之后，我们现在将继续我们的工作，基于对所涉及的分子机制的准确鉴定，开发和改进新型CRP阻断剂。然后，这些新的药物将在体外和体内的炎症性疾病的动物模型中进行筛选和测试，并最终代表一类新的抗炎剂转移到临床环境中。

C-reactive protein (CRP) is a highly conserved pentameric protein and is the prototypic acute phase protein. Recently it has been identified not only as a marker, but also causal factor of the inflammatory response. We could previously show in vitro and in vivo that in inflamed tissue local cell damage and membrane changes lead to dissociation of the circulating pentameric CRP (pCRP) into its monomeric subunits (monomeric=mCRP). The resulting mCRP is deposited in the area of inflammation and leads to a localized aggravation of the existing inflammatory response. The identification of CRP as locally activated pro-inflammatory system lead to the development of novel anti-inflammatory therapeutic strategies by us. These are targeting the dissociation process from pCRP to mCRP by stabilizing CRP with 1,6-bis-(Phosphocholin)-hexan, a chemically modified derivative of the CRP ligand phosphocholin. In our previous in vivo proof-of-concept study we could demonstrate the anti-inflammatory potential of this therapeutic concept. In this project we will now analyse the molecular mechanisms by which mCRP modulates inflammation. With site directed mutagenesis of CRP we will identify the pro-inflammatory sequences within the CRP primary structure and the role of relevant binding sites for described interaction partners of CRP in inflammation. This will allow for a better understanding of the underlying molecular mechanisms that in turn will allow for the identification of novel therapeutic approaches, as well as improving our existing therapeutic agents. After the identification of a novel pathological pro-inflammatory mechanism in our previous work and the proof-of-concept of the effectiveness of therapeutically targeting CRP we will now continue our work by developing and improving novel CRP-blocking agents based on the exact identification of the involved molecular mechanisms. These novel agents will then be screened and tested in in vitro and in vivo in animal models of inflammatory diseases and will ultimately represent a novel class of anti-inflammatory agents to be transferred into the clinical setting.