TRP Channels and Air Pollution

项目摘要/摘要： 对许多人来说，呼吸污染空气中不健康的颗粒物(PM)是不可避免的。目前， 我们对暴露与PM的许多不良健康影响有关的特定生化相互作用的知识 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，我们将在我们的 关于PM如何对肺部造成有害影响的工作建立了一个新的机制范例，包括 瞬时受体电位锚蛋白-1(TRPA1)、黑素抑素-8(TRPM8)和香草素-1(TRPV1)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有关的影响。因此，一个持续的- 对这一机械论范式的深入评估有可能为理解提供至关重要的知识 与PM相关的呼吸不适的基础，并加深我们对确切原因的理解 TRP通道对环境敏感型肺部疾病，如哮喘。此外，通过建立 调节与色氨酸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，以可能治疗和/或预防 环境肺病。 目前的研究结果表明，TRPA1、M8和V1在人类体内的差异激活 PM产生的肺细胞与促炎和其他影响人类呼吸道疾病的反应相结合- 相关的途径和表型，在这里通常被称为“PM毒性”。此外，还有一些物种-- 对PM的Trp通道反应的特异性差异，表明啮齿动物可能不能适当地模拟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械发现，以及开发有效的干预措施。最后，我们有 发现TRPA1、M8和V1单核苷酸多态(SNPs)可以调节细胞对 某些形式的PM，以及表面上会导致儿童哮喘症状控制较差。另外，TRPV1 I585I/V SNP基因与哮喘和慢性鼻窦炎(CRS)的诊断和严重程度相关。 因此，对选定的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PM过敏的预后生物标志物，以及个性化的标准 医疗护理。我们的假设是：PM激活TRPA1、M8和/或V1代表潜在的关键事件 PM的毒性效应具体目标是：1)确定物种的机制和重要性-- PM对Trp通道的特异性激活；2)阐明TRPV1 I585I/V的基础和毒理学意义 人肺上皮细胞依赖的TRPA1表达；以及3)量化TRPA1、M8和V1的影响 遗传学与哮喘环境恶化的关系。

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.