Developing a non-animal model system to investigate bitter tastants as new treatments for asthma

开发非动物模型系统来研究促苦味剂作为哮喘的新疗法

• 批准号: NC/M001504/1
• 负责人: Robin Williams
• 金额: $ 12.6万
• 依托单位: Royal Holloway University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FM001504%2F1
• 关键词: Developing; non; animal; model; system

The recent observation that bitter tasting compounds cause the opening of airways in the lung suggest a role for these compounds in the treatment of asthma. This is unexpected, since bitter taste detection was thought act to protect animals (including humans) from ingesting harmful, often bitter, compounds. Bitter tasting compounds are detected by a family of receptors called TAS2Rs that are found on the tongue. Intriguingly, however, it remains unclear if these TAS2Rs are involved in asthma treatment, or if this effect occurs through unidentified proteins. Increasing evidence suggests that these compounds may act through TAS2R independent targets, but these targets are still to be discovered. Research into bitter compounds and the way they work in asthma has focused on using lung tissue obtained from guinea pigs and mice, but also from humans. This research involves using this animal tissue to identify the process that bitter compounds trigger to cause muscle relaxation (related to relieving asthma induction). Using this approach, it was expected that the effect of each bitter compound could be mapped, and resulting information used to develop improved treatments for chronic asthma. Unfortunately, to date, bitter tasting compounds have been shown to mediate their dilatory effects in multiple ways, some acting independently of known TAS2Rs-dependent processes within these animal tissues. Identifying these mechanisms is thus highly important.Developing alternate non-animal systems to investigate the mechanisms of bitter tasting compounds will significantly reduce the use of animals in this research area. This research will also provide experimental approaches unavailable in animal models leading to breakthroughs in the treatment of asthma. We propose to develop a two stage system bitter tastant research, initially using the social amoeba Dictyostelium to identify how these tastants work, and then using human cells to confirm our discoveries are relevant to asthma treatment. We have shown that Dictyostelium can be successfully used to identify new mechanisms of action for compound relevant to human health. The effective use of this model is beyond doubt, as it has been used to find the mechanism of bipolar disorder drugs (Williams et al (2002) Nature, 417, 292-5; Williams (2005) Prog. in Neuro-Psychopharmacol. and Biol. Psychiatry 29, 1029-37), the mechanism of the most wildly used epilepsy treatment, valproic acid (Xu et al (2007) Euk Cell, 6, 899-90; Chang et al (2012) Disease Models and Mechanism, 5, 115-124; Chang et al (2013) Neurobiology of Disease, 62C, 296-306) and the underlying therapeutic mechanism of the MCT ketogenic diet (Chang et al (2013) Neuropharmacology, 69,105-14; Williams and Walker (2013) Biochem. Soc. Trans, 41,1625-8). It has also been used to identify novel molecular targets for two structurally independent bitter tastants been (Robery et al (2013) Journal of Cell Science, 126, 5465-76; Waheed et al (2014) British Journal of Pharmacology, 171, 2659-70). Hence therapeutically relevant targets for bitter compounds in the treatment of asthma will be identified in the project using Dictyostelium as an animal replacement model.Ultimately, our goal is to develop Dictyostelium as a non-animal system to uncover the mechanisms whereby bitter tasting compounds mediate their effects, to identify novel molecular targets for the treatment of asthma.

最近的观察表明，苦味化合物会导致肺部气道开放，这表明这些化合物在治疗哮喘中发挥了作用。这是出乎意料的，因为苦味检测被认为是保护动物（包括人类）免受摄入有害的、通常是苦味的化合物的影响。苦味化合物是由舌头上发现的一种名为TAS 2 R的受体家族检测到的。然而，有趣的是，目前还不清楚这些TAS 2 R是否参与哮喘治疗，或者这种作用是否通过未鉴定的蛋白质发生。越来越多的证据表明，这些化合物可能通过TAS 2 R非依赖性靶点发挥作用，但这些靶点仍有待发现。对苦味化合物及其在哮喘中作用方式的研究集中在使用豚鼠和小鼠的肺组织上，但也有来自人类的。这项研究涉及使用这种动物组织来确定苦味化合物引发肌肉松弛的过程（与缓解哮喘诱导有关）。使用这种方法，预计可以绘制出每种苦味化合物的效果，并将由此产生的信息用于开发改善慢性哮喘的治疗方法。不幸的是，迄今为止，苦味化合物已被证明以多种方式介导其扩张作用，一些作用独立于这些动物组织内已知的TAS 2 Rs依赖性过程。因此，确定这些机制非常重要。开发替代的非动物系统来研究苦味化合物的机制将显着减少该研究领域中动物的使用。这项研究还将提供在动物模型中无法获得的实验方法，从而在哮喘治疗方面取得突破。我们建议开发一个两阶段系统的苦味促味剂研究，首先使用社会阿米巴Dictyosteophila来确定这些促味剂如何工作，然后使用人类细胞来确认我们的发现与哮喘治疗有关。我们已经证明，Dictyosteroid可以成功地用于识别与人类健康相关的化合物的新作用机制。该模型的有效使用是毫无疑问的，因为它已被用于发现双相情感障碍药物的机制（威廉姆斯等人（2002）Nature，417，292-5;威廉姆斯（2005）Prog.神经精神药理学和Biol. Psychiatry 29，1029-37），最广泛使用的癫痫治疗的机制，丙戊酸（Xu等人（2007）Euk Cell，6，899-90; Chang等人（2012）Disease Models and Mechanism，5，115-124; Chang等人（2013）Neurobiology of Disease，62 C，296-306）和MCT生酮饮食的潜在治疗机制。（Chang等人（2013）Neuropharmacology，69，105 -14;威廉姆斯和步行者（Walker）（2013）Biochem. Soc. Trans，41，1625 -8）。它还被用于鉴定两种结构上独立的促苦味剂的新分子靶标（Robery等人（2013）Journal of Cell Science，126，5465-76; Waheed等人（2014）British Journal of Pharmacology，171，2659-70）。因此，本项目将使用Dictyosteopathy作为动物替代模型，确定苦味化合物治疗哮喘的治疗相关靶点。最终，我们的目标是开发Dictyosteopathy作为非动物系统，以揭示苦味化合物介导其作用的机制，以确定治疗哮喘的新分子靶点。