Mechanisms of inflammation by S100A12

该项目将描述一种新的人类促炎蛋白S100的生物学和功能特性。这种蛋白质是先天免疫系统的天然组成部分，在细胞中受炎症和感染介质的调节。我们的初步实验表明，这种蛋白可以激活肥大细胞。这些细胞存在于几乎所有的身体组织中，靠近血管和神经。这一位置使它们成为触发血管和炎症事件的首要目标。众所周知，它们在过敏和感染中具有重要作用，并在慢性炎症过程中具有拟议的作用。虽然肥大细胞激活在过敏反应中引起急性反应的机制已经被广泛接受，但它们在哮喘和其他慢性炎症性疾病中的激活方式几乎是未知的。我们将使用哮喘患者的肺活检来检测该蛋白的表达模式，并确定其对肺肥大细胞的影响。一个小鼠模型将被用来确定S100蛋白引起的炎症的特征以及肥大细胞在这一过程中的作用。结构研究将确定肥大细胞激活所需的蛋白质部分。我们将尝试识别肥大细胞上的它的受体，以使未来的研究能够确定该蛋白如何触发细胞产生组胺等介质以及那些导致血管变化的介质。这一知识可能会导致设计出能够调节这一过程的新药。该项目的结果将为慢性炎症过程提供新的知识，并可能导致设计新的策略来调节这些过程。研究涉及传染病和许多其他以慢性炎症为基础的疾病，包括哮喘、类风湿性关节炎、心血管疾病、囊性纤维化和感染。

This project will characterise the biological and functional properties of a novel human pro-inflammatory S100 protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells. These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location makes them prime targets to trigger vascular and inflammatory events. They are known to be important in allergy and infection and have a proposed role in chronic inflammatory processes. Although the mechanisms of mast cell activation contributing to acute responses in allergic reactions are well accepted, ways in which they are activated in asthma and other chronic inflammatory disease are virtually unknown. We will use lung biopsies from patients with asthma to detect patterns of expression of the protein and determine its effects on lung mast cells. A murine model will be used to define the characteristics of inflammation induced by the S100 protein and the role of mast cells in this process. Structural studies will define the parts of the protein necessary for mast cell activation. We will attempt to identify its receptor on mast cells to enable future studies to define how the protein triggers the cells to produce mediators such as histamine and those causing blood vessel changes. This knowledge could lead to design of novel drugs that could regulate this process. Results from this project will provide new knowledge of chronic inflammatory processes and could result in designing novel strategies to regulate these. Studies are relevant to infectious diseases and many other conditions with a chronic inflammatory basis, including asthma, rheumatoid arthritis, cardiovascular disease, cystic fibrosis and infection.