TRP Channels and Air Pollution

TRP 通道和空气污染

• 批准号: 10440374
• 负责人: Christopher A Reilly
• 金额: $ 60.95万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440374
• 关键词: ANK1 gene; Acute; Adverse effects; Affect; Agonist; Air; Air Pollutants; Air Pollution; Amino Acids; Asthma; Binding; Biochemical; Breathing; Caring; Cells; Child; Chimeric Proteins; Clinics and Hospitals; Coal; Coupled; Coupling; Data; Development; Diagnosis; Diesel Exhaust; Ectopic Expression; Electronics; Enrollment; Environment; Epithelial Cells; Etiology; Event; Exposure to; Genetic; Genotype; Goals; Health; Hospitalization; Human; Human Genetics; Hypersensitivity; Individual; Inflammatory; Inflammatory Response; Intervention; Ion Channel; Knowledge; Leucine-Rich Repeat; Link; Liquid substance; Lung; Lung diseases; Malaise; Mediator; Medical; Modeling; Modification; Molecular; NF-kappa B; Nasal Epithelium; Natural Source; Nucleotides; Outcome; Particulate; Particulate Matter; Pathologic; Pathway interactions; Patient Self-Report; Pediatric Hospitals; Persons; Phenotype; Premature Mortality; Process; Prognostic Marker; Property; Research; Respiratory Disease; Risk; Rodent; Rodent Model; SNP genotyping; Sampling; Scheme; Severities; Single Nucleotide Polymorphism; Site; Symptoms; TRP channel; TRPA channel; TRPV1 gene; Toxic effect; Toxicology; Translating; Translations; Universities; Utah; Vanilloid; Work; airway epithelium; antagonist; asthma exacerbation; biomass smoke; bronchial epithelium; chronic respiratory disease; chronic rhinosinusitis; cigarette smoke; cytokine; cytotoxic; differential expression; effective intervention; environmental particulate; fine particles; fly ash; humanized mouse; improved; innovation; insight; marenostrin; mutant; novel; novel strategies; predictive marker; prevent; programs; recruit; respiratory; response; sensor

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.

项目摘要/摘要： 目前，对许多人来说，呼吸污染空气中的不健康颗粒物 (PM) 是不可避免的。 我们对特定生化相互作用的了解，这些相互作用与 PM 的许多不利健康影响有关 是不完整的，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基础上。 致力于建立一种新的机制范式来解释 PM 如何对肺部造成有害影响，包括 激活瞬时受体电位 ankyrin-1 (TRPA1)、melastatin-8 (TRPM8) 和 vanilloid-1 (TRPV1) 我们的工作表明，不同类型的 PM 激活不同的 TRP 通道，通常会导致特定的离子通道。 与人类呼吸道疾病因果关系和急性恶化相关的影响因此，持续存在。 对这种机械范式的深入评估有可能为理解提供关键知识 与 PM 相关的呼吸系统不适的基础，并进一步了解其确切贡献 TRP 会导致环境敏感的肺部疾病，例如哮喘。 调节与 TRP 通道激活相关的病理生理结果的基本机制 总理，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 环境性肺部疾病。 目前的研究是基于以下结果：TRPA1、M8 和 V1 在人类中的差异激活 PM 引起的肺细胞与促炎反应和其他影响人类呼吸道疾病的反应有关 相关途径和表型，本文通常称为“PM 毒性”。 TRP 通道对 PM 反应的具体差异，表明啮齿类动物可能无法充分模拟 TRP- 我们认为这可能是转化的一个重要障碍。 从啮齿动物模型到人类的机制研究结果，以及开发有效的干预措施。 发现 TRPA1、M8 和 V1 单核苷酸多态性 (SNP) 可以调节细胞对 某些形式的 PM，表面上还会导致儿童哮喘症状控制较差。 I585I/V SNP 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，评估选定的 TRP SNP 影响细胞对 PM 反应的机制，以及 哮喘控制，可以揭示对 PM 过敏的预后生物标志物以及个性化标准 我们的假设是：PM 激活 TRPA1、M8 和/或 V1 代表潜在的关键事件。 PM 的毒性作用的具体目标是： 1) 确定物种的机制和重要性。 PM特异性TRP通道激活；2）阐明TRPV1 I585I/V-的基础和毒理学意义 人肺上皮细胞依赖性 TRPA1 表达；3) 量化 TRPA1、M8 和 V1 的影响 哮喘环境检查中的遗传学。

项目成果

Dynamic Expression of Transient Receptor Potential Vanilloid-3 and Integrated Signaling with Growth Factor Pathways during Lung Epithelial Wound Repair following Wood Smoke Particle and Other Forms of Lung Cell Injury.

• DOI: 10.1124/molpharm.121.000280
• 发表时间: 2021-09-01
• 期刊: Molecular pharmacology
• 影响因子: 3.6
• 作者: Burrell, Katherine L;Nguyen, Nam D;Reilly, Christopher A
• 通讯作者: Reilly, Christopher A

Steady-state estradiol triggers a unique innate immune response to allergen resulting in increased airway resistance.

• DOI: 10.1186/s13293-022-00483-7
• 发表时间: 2023-01-06
• 期刊: BIOLOGY OF SEX DIFFERENCES
• 影响因子: 7.9
• 作者: Warren, Kristi J. J.;Deering-Rice, Cassandra;Huecksteadt, Tom;Trivedi, Shubhanshi;Venosa, Alessandro;Reilly, Christopher;Sanders, Karl;Clayton, Frederic;Wyatt, Todd A. A.;Poole, Jill A. A.;Heller, Nicola M. M.;Leung, Daniel;Paine III, Robert
• 通讯作者: Paine III, Robert

A bacterial source for mollusk pyrone polyketides.

• DOI: 10.1016/j.chembiol.2012.10.019
• 发表时间: 2013-01-24
• 期刊: Chemistry & biology
• 作者: Lin Z;Torres JP;Ammon MA;Marett L;Teichert RW;Reilly CA;Kwan JC;Hughen RW;Flores M;Tianero MD;Peraud O;Cox JE;Light AR;Villaraza AJ;Haygood MG;Concepcion GP;Olivera BM;Schmidt EW
• 通讯作者: Schmidt EW

Electrophilic components of diesel exhaust particles (DEP) activate transient receptor potential ankyrin-1 (TRPA1): a probable mechanism of acute pulmonary toxicity for DEP.

• DOI: 10.1021/tx200123z
• 发表时间: 2011-06-20
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Deering-Rice CE;Romero EG;Shapiro D;Hughen RW;Light AR;Yost GS;Veranth JM;Reilly CA
• 通讯作者: Reilly CA

Contributions of TRPV1, endovanilloids, and endoplasmic reticulum stress in lung cell death in vitro and lung injury.

• DOI: 10.1152/ajplung.00231.2011
• 发表时间: 2012
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: K. Thomas;Jessica K. Roberts;C. Deering-Rice;Erin G. Romero;R. Dull;Jeewoo Lee;G. Yost;C. Reilly