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.

项目摘要 哮喘是由于遗传背景与环境之间的复杂相互作用引起的 触发器。 17q21哮喘易感性基因座通过 ORMDL3。 ORMDL3调节丝氨酸甲虫COA转移酶（SPT），临界酶 从头合成鞘脂。我们证明了降低的SPT活性导致 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相关哮喘的动物模型中会改变。我们有 最近表明哮喘儿童鞘脂合成降低，尤其是在 哮喘的存在风险17q21基因型。 17Q21基因型也与 人类鼻病毒（HRV）呼吸道感染后发生哮喘。这很重要 因为HRV也是哮喘攻击的最常见触发因素。 在小鼠和气道上皮细胞中的初步数据支持的支持 HRV感染与鞘脂之间的鞘脂水平的相似性和基因表达 缺乏症，我们假设HRV感染会进一步损害鞘脂的合成。我们 建议研究HRV对哮喘和患有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 在哮喘发病机理中，通过共性和强关联预测 哮喘的17q21基因型。提出了两个具体目标来评估总体假设 从头合成途径不仅对哮喘发病机理，而且是至关重要的 还响应哮喘攻击最常见的触发因素。在AIM 1中，我们将确定 哮喘和HRV感染儿童呼吸道中的鞘脂合成。 鞘脂将在获得的鼻液，血液和基因表达中评估 在解决HRV触发的哮喘发作期间和之后的儿童。在一个subiaim中，我们 将评估HRV对鞘脂代谢和基因表达的影响 人类气道上皮细胞（HAEC），具有纯合的17q21哮喘变异 这导致哮喘儿童的血液鞘脂减少。来自既定的HAEC 来自成人捐助者和鼻刷的生物库，这些孩子都在空气中生长 界面将被HRV和RSV感染，并评估对鞘脂合成的影响。 对于AIM 2，我们将检验以下假设：鞘脂介质的比例改变了 鞘氨醇1-磷酸盐和1磷酸盐，我们在SPT缺乏和 患有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 研究不仅告知鞘脂脂在哮喘和哮喘发病机理中的作用 与最常见的触发因素有关，但可能导致涉及的新治疗方法 鞘脂代谢。