Respiratory sphingolipid synthesis involved in airway hyperreactivity and viral-triggered asthma

呼吸鞘脂合成参与气道高反应性和病毒引发的哮喘

• 批准号: 10660726
• 负责人: Stefan Worgall
• 金额: $ 88.44万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-08 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660726
• 关键词: 17q21; Adult; Affect; Agonist; Air; Animal Model; Asthma; Blood; Cell model; Cells; Cellular Stress; Child; Childhood Asthma; Coenzyme A-Transferases; Complex; Data; Development; Disease; Enzymes; Epithelial Cells; Etiology; Gene Expression; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genotype; High Pressure Liquid Chromatography; Human; Immune response; Impairment; In Vitro; Incidence; Infection; Innate Immune Response; Knowledge; Label; Link; Liquid substance; Lung; Mediating; Mediator; Metabolic; Metabolic Pathway; Metabolism; Mus; Nasal Epithelium; Nose; Palmitoyl Coenzyme A; Pathogenesis; Pathway interactions; Play; Production; Resolution; Respiratory System; Respiratory Tract Infections; Rhinovirus; Rhinovirus infection; Risk; Role; Serine; Shapes; Slice; Sphingolipids; Sphingosine-1-Phosphate Receptor; Stable Isotope Labeling; Subgroup; Susceptibility Gene; Testing; Variant; Viral; Viral Respiratory Tract Infection; Work; airway epithelium; airway hyperresponsiveness; asthma exacerbation; asthmatic; asthmatic airway; biobank; chronic respiratory disease; cohort; constriction; dihydrosphingosine 1-phosphate; early childhood; monocyte; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; repository; respiratory; response; risk variant; sphingosine 1-phosphate; tandem mass spectrometry; transcriptome sequencing

PROJECT SUMMARY Asthma results from a complex interplay between genetic background and environmental triggers. The 17q21 asthma susceptibility locus is strongly linked to childhood asthma through ORMDL3. ORMDL3 regulates serine-palmitoyl CoA transferase (SPT), the critical enzyme for the de novo synthesis of sphingolipids. We demonstrated that decreased SPT activity leads to airway hyperreactivity. There has since been increasing evidence that sphingolipid metabolism is altered in airway epithelial cells and animal models of ORMDL3-associated asthma. We have recently shown that children with asthma have decreased sphingolipid synthesis, especially in the presence of asthma risk 17q21 genotypes. 17q21 genotypes are also linked to the risk of developing asthma following respiratory infections with human rhinovirus (HRV). This is relevant as HRV is also the most common trigger for asthma attacks. Supported by preliminary data in mice and airway epithelial cells demonstrating strong similarities in sphingolipid levels and gene expression between HRV infection and sphingolipid deficiency, we hypothesize that HRV infection can further impair sphingolipid synthesis. We propose to study the effects of HRV on sphingolipid synthesis in children with asthma and airway epithelial cells. These studies could then further solidify the central role of sphingolipids in asthma pathogenesis that has been predicted by the commonality and the strong association of 17q21 genotypes to asthma. Two specific aims are proposed to assess the overall hypothesis that the sphingolipid de novo synthesis pathway is critical not only for asthma pathogenesis but also in response to the most common trigger for asthma attacks. In Aim 1, we will determine sphingolipid synthesis in the respiratory tract in children with asthma and HRV infection. Sphingolipids will be assessed in nasal fluid, blood, and gene expression in nasal cells obtained from children during and after the resolution of HRV-triggered asthma attacks. In a subaim, we will evaluate the effects of HRV on sphingolipid metabolism and gene expression in primary human airway epithelial cells (HAEC) with homozygous for a common 17q21 asthma variation that leads to decreased blood sphingolipids in children with asthma. HAEC from an established biorepository from adult donors and nasal brushings from children all grown at air-liquid interface will be infected with HRV and RSV and evaluated for effects on sphingolipid synthesis. For Aim 2, we will test the hypothesis that the altered ratio of the sphingolipid mediator sphingosine 1-phosphate and sphinganine 1 phosphate, which we found in SPT deficiency and children with the 17q21 asthma risk genotypes, leads to airway hyperreactivity. Overall, these studies not only inform on the role of sphingolipids in the pathogenesis of asthma and the relation to its most common trigger but may lead to new therapeutic approaches involving sphingolipid metabolism.

项目概要 哮喘是遗传背景和环境之间复杂相互作用的结果 触发器。 17q21 哮喘易感位点通过以下方式与儿童哮喘密切相关： ORMDL3。 ORMDL3 调节丝氨酸棕榈酰辅酶 A 转移酶 (SPT)，这是 鞘脂的从头合成。我们证明，SPT 活性降低会导致 气道高反应性。此后越来越多的证据表明鞘脂代谢 在气道上皮细胞和 ORMDL3 相关哮喘动物模型中发生改变。我们有 最近表明，哮喘儿童的鞘脂合成减少，尤其是 存在哮喘风险 17q21 基因型。 17q21 基因型也与以下风险有关： 人鼻病毒 (HRV) 呼吸道感染后出现哮喘。这是相关的 因为 HRV 也是哮喘发作的最常见诱因。 小鼠和气道上皮细胞的初步数据表明， HRV 感染和鞘脂之间鞘脂水平和基因表达的相似性 由于缺乏，我们假设 HRV 感染会进一步损害鞘脂合成。我们 提议研究 HRV 对哮喘儿童鞘脂合成的影响 气道上皮细胞。这些研究可以进一步巩固鞘脂的核心作用 哮喘发病机制已通过共性和强关联性预测 17q21 基因型与哮喘的关系。提出了两个具体目标来评估总体假设 鞘脂从头合成途径不仅对于哮喘发病机制至关重要，而且对于 也是针对哮喘发作最常见的诱因。在目标 1 中，我们将确定 哮喘和 HRV 感染儿童呼吸道中鞘脂的合成。 将评估鼻液、血液中的鞘脂以及获得的鼻细胞中的基因表达 来自儿童 HRV 引发的哮喘发作期间和缓解后的数据。在一个子目标中，我们 将评估 HRV 对原代细胞中鞘脂代谢和基因表达的影响 具有常见 17q21 哮喘变异纯合子的人气道上皮细胞 (HAEC) 这会导致哮喘儿童血液中的鞘脂减少。 HAEC 来自一家成熟的 来自成人捐赠者的生物储存库和来自儿童的鼻刷，均在气液条件下生长 界面将被 HRV 和 RSV 感染，并评估对鞘脂合成的影响。 对于目标 2，我们将检验以下假设：鞘脂介质的比例发生改变 1-磷酸鞘氨醇和 1 磷酸鞘氨醇，我们在 SPT 缺乏症和 具有 17q21 哮喘风险基因型的儿童会导致气道高反应性。总体而言，这些 研究不仅揭示了鞘脂在哮喘发病机制中的作用， 与其最常见的触发因素有关，但可能会导致新的治疗方法，包括 鞘脂代谢。