Role of osteopontin in innate immunity during infections and inflammation

项目摘要/摘要： 骨桥蛋白(OPN)参与多种炎症性疾病的发病机制，包括 感染、自身免疫性疾病、癌症和其他伴随炎症的疾病。OPN主要是 被认为是一种促炎分子，通常被认为能诱导免疫反应。然而， 最近的研究表明，OPN有时作为一种抗炎分子发挥作用，以及OPN是如何 施瓦茨的角色完全难以捉摸。了解OPN如何扮演双面角色至关重要，尤其是因为 OPN作为一种药物靶点和多种疾病的疾病标志物而备受关注。为此，这 拟议中的研究试图了解OPN切换免疫反应的分子机制， 并将使用OPN突变体的五个品系用活体动物疾病模型验证机制假说 老鼠。 我们的中心假设是：细胞内OPN(IOPN)是使OPN的角色在亲-亲之间转换的主要参与者 发炎和抗炎。在这里，OPN有两种OPN亚型，分泌的(SOPN)和细胞内的 (IOPN)。在过去，我们首先成功地生化证实了iOPN的存在，并揭示了 IOPN的产生机制及其功能。作为iOPN领域的先驱，我们一直在不断地 发现iOPN以及sOPN的新角色。要以一种特定于异构体的方式研究OPN，它是 重要的是要有专门表达两种亚型之一的细胞和鼠系。我们目前正在 不仅配备了iOPN和sOPN表达载体，而且我们将使用多个OPN突变小鼠系， 这使得我们有可能评估OPN在体内疾病模型中的异构体特异性作用。 这项拟议研究的目的是确定iOPN如何作为抗炎分子发挥作用；以及 该项目的长期目标是阐明iOPN和sOPN在炎症中的作用。

PROJECT SUMMARY/ABSTRACT  Osteopontin (OPN) is involved in the pathogenesis of a wide variety of inflammatory disorders, including infections, autoimmune diseases, cancer, and other diseases accompanied with inflammation. OPN is primarily considered to be a pro-inflammatory molecule and is generally known to induce immune responses. However, recent studies suggested that OPN occasionally functions as an anti-inflammatory molecule, and how OPN switches its role is entirely elusive. It is critical to know how OPN plays the two-sided role, particularly because OPN attracts attentions as a pharmaceutical target and a disease marker in various diseases. To this end, this proposed study seeks to understand the molecular mechanism by which OPN switches immune responses, and will verify the mechanistic hypothesis with in vivo animal disease models using five lines of OPN mutant mice. Our central hypothesis is: Intracellular OPN (iOPN) is a major player to make OPN’s role switch between pro- inflammatory and anti-inflammatory. Here, OPN has two OPN isoforms, secreted (sOPN) and intracellular (iOPN). In the past, we first succeeded to biochemically confirm the presence of iOPN, and revealed the mechanism of iOPN’s generation and its functions. As a pioneer of the iOPN field, we have been continuously discovering new roles of iOPN, as well as those of sOPN. To study OPN in an isoform-specific fashion, it is important to have cells and mouse lines that exclusively express one of two isoforms. We are currently equipped not only with iOPN and sOPN expression vectors, but we will use multiple lines of OPN mutant mice, which make it possible for us to evaluate the isoform-specific role of OPN in in vivo disease models. The objective of this proposed study is to determine how iOPN functions as an anti-inflammatory molecule; and the long-term goal of this project is to elucidate the roles of iOPN and sOPN in inflammation.