CRAC channel-dependent calcium microdomains and mast cell function in health and disease

在过去的20年里，英国的过敏患者明显增加。过敏有各种各样的表现，但两种特别常见的是哮喘和过敏性鼻炎/鼻息肉病。最近的数据显示，近30%的英国人在某种程度上患有过敏性鼻炎和息肉病，这些疾病会导致鼻子发炎，对生活质量造成严重影响，包括鼻塞和嗅觉完全丧失。这些疾病都是由容易触发的免疫系统引起的，罪魁祸首是肥大细胞。有效治疗这些医学问题需要详细了解细胞生理学的基本过程，将其应用于肥大细胞可能会导致对抗过敏的新疗法。众所周知，就像几乎所有动物细胞一样，钙的增加会激活肥大细胞，钙的增加会导致肥大细胞释放一系列化学物质，这些化学物质会招募和刺激其他免疫细胞、血管和气道肌肉。如果不加以控制，可能会造成严重的局部组织损伤。像其他细胞一样，肥大细胞可以通过以下两种方式之一来增加钙含量：钙可以从细胞外进入，也可以从细胞内的储存囊中释放出来。这些储存囊只含有少量的钙，钙进入肥大细胞是维持反应的关键。钙的进入是由细胞表面的微孔控制的，这些微孔根据内部信号打开或关闭。这些孔隙被称为CRAC通道。缺乏CRAC通道的动物肥大细胞功能严重受损。这项提议的目的是了解，在一个非常基本的水平上，CRAC通道如何激活人类鼻肥大细胞，以及该通道和随后的肥大细胞反应如何在过敏中发生变化。这项工作将增强我们对肥大细胞的理解，以及它们是如何被调节的。它还将揭示当这些细胞出现问题时会发生什么，并可能为过敏性疾病的药物治疗确定新的治疗靶点。

The last 20 years have seen a marked rise in allergy sufferers in the U.K. Allergies come in various disguises but two particularly common ones are asthma and allergic rhinitis/nasal polyposis. Recent figures indicate that almost 30% of the U.K. population suffer, at some time, from allergic rhinitis and polyposis, ailments that result in inflammation within the nose, with serious consequences on quality of life including full nasal obstruction and complete loss of smell. These disorders arise from a trigger-happy immune system, with the main culprit being the mast cell. Effective treatment of these medical problems requires detailed understanding of fundamental processes in cell physiology and the application of this to mast cells may lead to new therapies for combating allergies. It is known that an increase in calcium activates the mast cell, as it does in virtually all animal cells, and that the calcium rise causes the mast cell to release a battery of chemicals that recruit and stimulate other immune cells, blood vessels and airway muscle. If unchecked, this can produce substantial local tissue damage. Like other cells, mast cells can increase their calcium levels in one of two ways: calcium can enter from outside the cell or it can be released from storage sacs inside the cell. These storage sacs contain only a small amount of calcium and it is calcium entry into the mast cell that is key for maintaining the responses. Calcium entry is controlled by tiny pores in the cell surface that open or close in response to internal signals. These pores are called the CRAC channel. Animals lacking the CRAC channel have severely compromised mast cell function. The aim of this proposal is to understand how, at a very fundamental level, the CRAC channel activates human nasal mast cells and how the channel and subsequent mast cell responses change in allergy. This work will enhance our understanding of mast cells, and how they are regulated. It will also shed new light on what happens when things go wrong with these cells and may identify new therapeutic targets for drug therapy for allergic disorders.