Complement factor H related protein 1 (FHR1): regulator of inflammation

所谓的无菌炎症是退行性疾病的核心机制，对公众健康有很大影响，如年龄相关性黄斑变性（AMD）。作为一种基本机制，损伤/坏死细胞或细胞外沉积物触发免疫机制，包括单核吞噬细胞的细胞免疫反应。这是如何引起的尚不清楚。血浆蛋白因子H相关蛋白-1（人类中的FHR1；小鼠中的FHRE）识别这些危险信号。FHR1结合受损或退行性表面，然后可通过质膜受体、CR3和EMR2直接激活单核细胞。鉴于这些观察结果，我们看到FHR1在慢性炎性退行性疾病中的突出作用；她在AMD。我们希望阐明FHR1如何结合表面，激活免疫活性细胞质膜中的受体，在血浆水平上与疾病相关，并参与导致AMD无菌炎症和自身炎症的一系列事件。为了翻译，我们将分析人体组织中的FHR1信号。在前期研究中，我们发现AMD患者眼睛中的Drusen中存在FHR1， AMD小鼠模型中存在FHRE。因此，我们假设一种新的功能机制被视为fhr1依赖性炎症，其中单核细胞和具有免疫细胞样特性的视网膜细胞发挥积极作用。在AMD中，FHR1的染色体缺失具有保护作用，这一事实支持了这一观点。因此，我们的目标是通过体外和体内研究FHR1在炎症中的分子作用，期望在AMD中找到新的治疗靶点。

The so-called sterile inflammation is a central mechanism in degenerative diseases with large impact into public health such as age-related macular degeneration (AMD). As a basic mechanism, injured/necrotic cells or extracellular deposits trigger immune mechanisms, including cellular immune responses by mononuclear phagocytes. How this is induced is still not clear. The plasma protein Factor H related protein-1 (FHR1 in humans; FHRE in mice) recognizes these danger signals. FHR1 binds to damaged or degenerative surfaces and can then directly activate monocytes via plasma membrane receptors, CR3 and EMR2. Given these observations, we see a prominent role of FHR1 in chronic inflammatory degenerative diseases; her in AMD. We want to clarify how FHR1 binds to surfaces, activates receptors in the plasma membrane of immune competent cells, relates in plasma levels to diseases and participates in the chain of events leading to sterile inflammation and auto-inflammation in AMD. For translation, we will analyze human tissues with respect to FHR1 signaling. In preliminary studies, we found FHR1 present in Drusen in eyes of AMD patients, FHRE in mouse models for AMD. Therefore, we assume a new functional mechanism seen as FHR1-dependent inflammation in which monocytes and retinal cells with immune cell-like properties play an active role. This is supported by the fact that in AMD the chromosomal deletion of FHR1 is protective. For that reason, we aim to investigate the molecular role of FHR1 in inflammation in vitro and in vivo and expect to find a new treatment target in AMD.