TRP Channels and Air Pollution

项目概要/摘要： 对许多人来说，吸入污染空气中不健康的颗粒物（PM）是不可避免的。目前， 我们对特定的生物化学相互作用的了解，这些相互作用将暴露于PM的许多不利健康影响联系起来 我们直接治疗和/或预防这些影响的能力也是不完整的。在这项研究中，我们将建立在我们的 工作建立了一个新的机制范式，PM如何在肺部造成有害影响，包括 瞬时受体电位锚蛋白-1（TRPA 1）、melastatin-8（TRPM 8）和香草素-1（TRPV 1）的激活 离子通道我们的工作表明，不同类型的PM激活不同的TRP通道，通常导致特定的 与人类呼吸道疾病病因和急性加重相关的影响。因此，一个持续的- 深入评估这种机制范式有可能为理解提供关键知识 与PM相关的呼吸道不适的基础，并进一步了解PM的确切贡献 TRP通道对环境敏感的肺部疾病，如哮喘。此外，通过建立 调节与TRP通道激活相关的病理生理结果的基本机制， PM，我们的研究可以揭示开发干预措施的创新策略， 环境性肺病 目前的研究的动机是结果表明，TRPA 1，M8和V1在人类中的差异激活 肺细胞的PM是耦合到促炎和其他反应，影响人类呼吸道疾病- 相关途径和表型，在本文中通常称为“PM毒性”。此外，还有一些物种- TRP通道对PM反应的具体差异，表明啮齿动物可能无法充分模拟TRP- PM对人体毒性的依赖机制。我们认为这可能是翻译的一个重要障碍 从啮齿动物模型到人类的机制研究结果，并制定有效的干预措施。我们终于有 发现TRPA 1，M8和V1单核苷酸多态性（SNP）可以调节细胞对 某些形式的PM，以及表面上导致儿童哮喘症状控制较差。此外，TRPV 1 I585 I/V基因型与哮喘和慢性鼻窦炎（CRS）的诊断和严重程度相关。 因此，选择的TRP SNP影响细胞对PM的反应的机制的评估，以及 哮喘控制，可以揭示对PM超敏反应的预后生物标志物， 医疗等我们的假设是：PM激活TRPA 1，M8和/或V1代表了一个关键事件， PM的毒性。具体目标是：1）确定机制和物种的意义- （2）阐明TRPV 1 I585 I/V的基础和毒理学意义。 人肺上皮细胞的依赖性TRPA 1表达;和3）定量TRPA 1、M8和V1的影响 遗传学在哮喘环境恶化中的作用

Project Summary/Abstract: Breathing unhealthy amounts of particulate matter (PM) in polluted air is unavoidable for many people. Currently, our knowledge of specific biochemical interactions that link exposure to the many adverse health effects of PM is incomplete, as is our ability to directly treat and/or prevent these effects. In this study we will build upon our work establishing a novel mechanistic paradigm for how PM can cause deleterious effects in the lungs, involving activation of the transient receptor potential ankyrin-1 (TRPA1), melastatin-8 (TRPM8) and vanilloid-1 (TRPV1) ion channels. Our work shows that different types of PM activate different TRP channels, often leading to specific effects that are relevant to human respiratory disease causation and acute exacerbation. Thus, a continued in- depth assessment of this mechanistic paradigm has the potential to provide crucial knowledge for understanding the basis for respiratory malaise associated with PM, and to further our understanding of the precise contributions of TRP channels to environmentally-sensitive lung diseases such as asthma. Additionally, by establishing fundamental mechanisms that regulate pathophysiological outcomes associated with TRP channel activation by PM, our research could reveal innovative strategies for developing interventions to possibly treat and/or prevent environmental lung diseases. The current studies are motivated by results showing that differential activation of TRPA1, M8, and V1 in human lung cells by PM is coupled to pro-inflammatory and other responses that affect human respiratory disease- related pathways and phenotypes, generally referred to herein as “PM toxicity.” Further, there are species- specific differences in TRP channel responses to PM, suggesting that rodents may not adequately model TRP- dependent mechanisms of PM toxicity in humans. We opine this could be an important barrier for translating mechanistic findings from rodent models to humans, and for developing effective interventions. Finally, we have found that TRPA1, M8, and V1 single-nucleotide polymorphisms (SNPs) can modulate cellular responses to certain forms of PM, as well as ostensibly cause poorer asthma symptom control in children. Also, the TRPV1 I585I/V SNP genotype correlates with the diagnosis and severity of asthma and chronic rhinosinusitis (CRS). Thus, assessment of mechanisms by which selected TRP SNPs affect cellular responses to PM, as well as asthma control, could reveal prognostic biomarkers of hypersensitivity to PM, and criteria for personalizing medical care. Our hypothesis is: Activation of TRPA1, M8 and/or V1 by PM represents a pivotal event underlying the toxic effects of PM. The specific aims are to: 1) Determine mechanisms and the significance of species- specific TRP channel activation by PM; 2) Elucidate the basis and toxicological significance of TRPV1 I585I/V- dependent TRPA1 expression by human lung epithelial cells; and 3) Quantify the impact of TRPA1, M8, and V1 genetics in environmental exacerbation of asthma.