Role of osteopontin in innate immunity during infections and inflammation

项目总结/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 被认为是促炎分子，并且通常已知诱导免疫应答。然而，在这方面， 最近的研究表明，骨桥蛋白偶尔作为一种抗炎分子发挥作用， 转换角色是完全难以捉摸的。关键是要知道OPN如何发挥双面作用，特别是因为 骨桥蛋白作为一种药物靶点和疾病标志物在多种疾病中引起了人们的关注。为此， 拟议的研究旨在了解OPN转换免疫反应的分子机制， 并将使用五种OPN突变体系的体内动物疾病模型来验证机制假说 小鼠 我们的中心假设是：细胞内OPN（iOPN）是使OPN在亲- 炎症和抗炎。在这里，OPN有两种OPN亚型，分泌型（sOPN）和细胞内型（sOPN）。 （iOPN）。在过去，我们首先成功地从生物化学上证实了iOPN的存在，并揭示了iOPN的作用机制。 iOPN的产生机制及其功能。作为iOPN领域的先驱，我们一直致力于 发现iOPN和sOPN的新作用。为了以异构体特异性的方式研究OPN， 重要的是，具有仅表达两种同种型之一的细胞和小鼠系。我们目前正在 不仅配备有iOPN和sOPN表达载体，而且我们将使用多系OPN突变小鼠， 这使得我们有可能评估OPN在体内疾病模型中的同种型特异性作用。 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.