MICA: CRAC channels, Ca2+ signalling and allergy

MICA：CRAC 通道、Ca2 信号传导和过敏

• 批准号: MR/L01047X/1
• 负责人: Anant Parekh
• 金额: $ 164.23万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL01047X%2F1
• 关键词: MICA; CRAC; channels; Ca2+; signalling

Allergies have reached epidemic levels in the UK, with almost 30% of the population estimated to suffer from allergy at some point in their lifetime. Moreover, the problem is not going to disappear because new allergies are being reported. So far, there has been disappointingly little progress with regard to treating allergies. Allergic reactions arise from an over-zealous immune system, with mast cells playing a particularly important role. Mast cells can be activated by harmless stimuli, such as pollen or animal fur, and this leads to an exaggerated response, which includes the excessive release of chemicals which affect the airways, blood vessels and stimulate other immune cells resulting in a chronic inflammation. Mast cells activate when tiny pores (channels) in their surface open, letting calcium ions flood into the cell. Controlling these pores is therefore a very effective way to manage mast cells. We have recently identified new mechanisms that control calcium entry and established how the incoming calcium activates mast cell responses. More importantly, we have developed a new strategy for manipulating mast cell activity and which could be useful in treating nasal polyposis, an inflammatory response in the upper airways sustained by mast cells.We plan systematic studies to dissect out the molecular pathways that control the calcium channel in healthy mast cells and how these processes are altered in human disease (polyposis and dermatitis). We will also test our new therapeutic strategy for controlling mast cell activation, using a novel system we have developed that is relevant to the real disease situation.

过敏症在英国已经达到了流行病的水平，估计有近30%的人口在一生中的某个时候患有过敏症。此外，这个问题不会因为新的过敏报告而消失。到目前为止，在治疗过敏方面进展甚微。过敏反应是由过度活跃的免疫系统引起的，其中肥大细胞起着特别重要的作用。肥大细胞可以被无害的刺激激活，如花粉或动物皮毛，这导致了过度的反应，其中包括过度释放影响气道，血管和刺激其他免疫细胞的化学物质，导致慢性炎症。当肥大细胞表面的微孔（通道）打开时，肥大细胞就会激活，让钙离子涌入细胞。因此，控制这些孔是管理肥大细胞的非常有效的方法。我们最近发现了控制钙进入的新机制，并确定了进入的钙如何激活肥大细胞反应。更重要的是，我们开发了一种操纵肥大细胞活性的新策略，这可能有助于治疗鼻息肉病，这是一种由肥大细胞维持的上呼吸道炎症反应。我们计划进行系统研究，以剖析控制健康肥大细胞中钙通道的分子途径，以及这些过程在人类疾病（息肉病和皮炎）中如何改变。我们还将测试我们控制肥大细胞活化的新治疗策略，使用我们开发的与真实的疾病情况相关的新系统。

项目成果

The Allergen Der p3 from House Dust Mite Stimulates Store-Operated Ca2+ Channels and Mast Cell Migration through PAR4 Receptors.

• DOI: 10.1016/j.molcel.2018.03.025
• 发表时间: 2018-04
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Yu-ping Lin;C. Nelson;H. Kramer;A. Parekh

Store-operated Ca2+ channels in airway epithelial cell function and implications for asthma.

• DOI: 10.1098/rstb.2015.0424
• 发表时间: 2016-08-05
• 期刊: Philosophical transactions of the Royal Society of London. Series B, Biological sciences
• 作者: Samanta K;Parekh AB
• 通讯作者: Parekh AB

Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca(2+) Signals.

• DOI: 10.1016/j.molcel.2016.11.011
• 发表时间: 2016-11-17
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Kar, Pulak;Mirams, Gary R.;Christian, Helen C.;Parekh, Anant B.
• 通讯作者: Parekh, Anant B.

Regulation of CRAC channels by Ca2+-dependent inactivation.

• DOI: 10.1016/j.ceca.2016.12.003
• 发表时间: 2017-05
• 期刊: Cell calcium
• 影响因子: 4
• 作者: A. Parekh

Distinct spatial Ca2+ signatures selectively activate different NFAT transcription factor isoforms.

• DOI: 10.1016/j.molcel.2015.02.027
• 发表时间: 2015-04-16
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Kar, Pulak;Parekh, Anant B.
• 通讯作者: Parekh, Anant B.