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Redox sensitive TRP ion channels in the interaction between human lung mast cells and oxidative stress

人肺肥大细胞与氧化应激相互作用中氧化还原敏感的TRP离子通道

基本信息

批准号：
MR/N02074X/1
负责人：
Harvinder Virk
金额：
$ 25.08万
依托单位：
University of Leicester
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN02074X%2F1
关键词：
Redox sensitive TRP ion channels

项目摘要

Asthma causes more than 1,000 deaths each year in the UK. For many people the currently available treatments do not adequately control their symptoms. There is evidence that a process called oxidative stress is important in this condition. Oxidative stress is a process when there are too many very reactive molecules called reactive oxygen species (ROS) and reactive nitrogen species (RNS) for the body to deal with, and they cause damage to the proteins and DNA inside cells. There are higher concentrations of these molecules produced in the airway of patients with asthma, and these can exacerbate inflammation and narrowing of the airways. Pulmonary fibrosis is another lung disease where ROS are thought to be involved in damaging the lung tissue, and abnormal healing following this damage may result in scarring of the lungs, preventing them from functioning properly.Mast cells are a type of cell that can cause inflammation by releasing chemicals in diseases such as anaphylaxis (a very severe and dangerous allergic reaction), asthma, rhinitis and eczema. These chemicals cause some of the symptoms of allergic diseases such as wheezing, excessive mucus, runny noses, and swelling of tissues. Mast cells also contribute to lung fibrosis. It has been found that ROS are produced in the process leading to release of chemicals by mast cells, and that using drugs that reduce ROS production might reduce the release of these chemicals; this could help to treat the symptoms of allergy and asthma, and also lung fibrosis. Although we know that there is probably too much ROS production in asthma, ROS also have important functions in normal healthy cells and tissues, and inhibiting them might also cause some unhelpful side effects too. That is why we believe it is important to investigate what regulates the production of ROS in inflammatory cells, particularly in mast cells, to help us develop new, effective and safe therapies, including for allergic conditions and fibrosis.In order for cells to be respond appropriately to oxidative stress and possibly regulate ROS production they need to be able to tell if there are too many ROS being produced; they need to be able to sense the presence of oxidative stress. Some proteins called transient receptor potential (TRP) channels are able to do this, and we have preliminary evidence from work performed in our lab, that they may be operating in mast cells from human lungs. We believe that they may be able to regulate human lung mast cell function, the production of ROS, as well as mediating both beneficial and detrimental cell activities in response to oxidative stress. Our research is aimed at testing these ideas to help develop better treatments for lung diseases that involve mast cells and oxidative stress including asthma and pulmonary fibrosis.My goals are to investigate how these channels are involved in mast cell function, including whether they can promote or reduce mast cell activation (mast cells are overactive in some diseases) in conditions of oxidative stress. I will also investigate whether the number of these channels in the bronchial tubes of patients with asthma is different to people without asthma.

在英国，哮喘每年导致1000多人死亡。对许多人来说，目前可用的治疗方法不能充分控制他们的症状。有证据表明，在这种情况下，一种被称为氧化应激的过程很重要。氧化应激是一种反应性很强的分子，称为活性氧（ROS）和活性氮（RNS），需要身体处理，它们会对细胞内的蛋白质和DNA造成损害的过程。哮喘患者的气道中产生的这些分子浓度更高，这些分子会加剧炎症和气道狭窄。肺纤维化是另一种肺部疾病，ROS被认为与肺组织损伤有关，这种损伤后的异常愈合可能导致肺部瘢痕形成，使其无法正常运作。肥大细胞是一种可以通过释放化学物质引起炎症的细胞，这些化学物质会导致过敏反应（一种非常严重和危险的过敏反应）、哮喘、鼻炎和湿疹等疾病。这些化学物质会引起过敏性疾病的一些症状，如喘息、粘液过多、流鼻涕和组织肿胀。肥大细胞也会导致肺纤维化。研究发现，ROS是在肥大细胞释放化学物质的过程中产生的，使用减少ROS产生的药物可能会减少这些化学物质的释放；这可能有助于治疗过敏和哮喘症状，以及肺纤维化。虽然我们知道哮喘中可能有过多的活性氧产生，但活性氧在正常健康细胞和组织中也有重要的功能，抑制它们也可能导致一些无益的副作用。这就是为什么我们认为研究是什么调节炎症细胞，特别是肥大细胞中ROS的产生，以帮助我们开发新的，有效和安全的治疗方法，包括过敏条件和纤维化，是很重要的。为了使细胞对氧化应激做出适当的反应并可能调节活性氧的产生它们需要能够判断是否产生了过多的活性氧；它们需要能够感知氧化应激的存在。一些被称为瞬时受体电位（TRP）通道的蛋白质能够做到这一点，我们从实验室的工作中获得了初步证据，表明它们可能在人类肺部的肥大细胞中起作用。我们认为，它们可能能够调节人肺肥大细胞的功能，ROS的产生，以及在氧化应激反应中介导有益和有害的细胞活动。我们的研究旨在测试这些想法，以帮助开发更好的治疗涉及肥大细胞和氧化应激的肺部疾病，包括哮喘和肺纤维化。我的目标是研究这些通道如何参与肥大细胞功能，包括它们是否可以促进或减少氧化应激条件下肥大细胞的激活（肥大细胞在某些疾病中过度活跃）。我还将调查哮喘患者支气管中这些通道的数量是否与非哮喘患者不同。