Role of ORMDL3 and ceramide in asthma severity

项目总结 哮喘的易感性以及哮喘的恶化受环境和众多基因的影响 变种。ORMDL3(酵母)样蛋白异构体3(ORMDL3)已被证明是导致这种情况的遗传因素之一 该基因的表达与过敏性哮喘有很强的相关性。从生理上讲，ORMDL3 是丝氨酸棕榈酰转移酶(Spt)的负调节因子，spt是从头合成过程中的限速酶。 神经酰胺，一种神经鞘糖脂的代谢物。然而，我们实验室公布的初步数据已经 提示在病理条件下，如哮喘，ORMDL3的上调意外增加 神经酰胺。室内粉尘螨(HDM)和交链孢霉(Alt)过敏性呼吸道疾病小鼠模型 总结人类过敏性哮喘的特征，我们发现ORMDL3和神经酰胺都增加了 并加重呼吸道炎症和高反应性(AHR)。 肺上皮细胞是吸入病原体和过敏原以及细胞过度凋亡的最初接触部位。 在肺上皮内形成称为克里奥拉小体的细胞聚集体，通常与 哮喘的严重程度。然而，人们对细胞凋亡过程的最初触发因素知之甚少。有趣的是，我发现 不仅神经酰胺升高，而且细胞凋亡和氧化应激(ROS)在变应原-肺组织中也被降低。 用SPT抑制剂myriocin(MyR)处理的小鼠。根据初步数据，我推测 在过敏性哮喘期间，ORMDL3的表达在肺上皮细胞中特异性上调，导致戏剧性的 鞘磷脂代谢物增加，尤其是神经酰胺。我认为神经酰胺的这种升高有助于 通过诱导细胞凋亡和/或氧化应激来加重过敏性哮喘，而靶向 ORMDL3-神经酰胺轴可减轻炎症、气道阻塞和AHR。为了检验这一假设，在Aim中 1，我将研究神经酰胺升高导致哮喘加重的机制。在目标2中，我 将研究全局或细胞自主的ORMDL3过表达在神经酰胺形成中的作用及其 在哮喘加重中的作用。 我的建议将增进对ORMDL3和神经酰胺在变态反应中的病理作用的理解 哮喘，神经酰胺水平升高与细胞凋亡或氧化应激和哮喘易感性有关，并可能 为潜在的治疗哮喘的新途径铺平道路。

PROJECT SUMMARY Susceptibility to asthma as well as its exacerbation are influenced by the environment and numerous genetic variations. ORM (yeast)-like protein isoform 3 (ORMDL3) has been shown to be one of genetic factors of this disease and there is a strong association between its expression and allergic asthma. Physiologically, ORMDL3 is a negative regulator of serine palmitoyltransferase (SPT), the rate-limiting enzyme in the de novo biosynthesis of ceramide, a central sphingolipid metabolite. However, published and preliminary data from our lab has suggested that under pathological conditions, such as asthma, upregulation of ORMDL3 unexpectedly increased ceramide. In house dust mite (HDM) and Alternaria alternata (Alt) mouse models of allergic airway disease that recapitulate the hallmarks of human allergic asthma, we found that both ORMDL3 and ceramide are increased in the lung and exacerbate airway inflammation and hyperreactivity (AHR). The lung epithelium is the initial site of contact for inhaled pathogens and allergens and excessive apoptosis within the lung epithelium forms cellular aggregates referred to as Creola bodies that commonly correlate with asthma severity. Yet, little is known of the initial trigger of the apoptotic process. Interestingly, I found that not only ceramide elevation but also apoptosis and oxidative stress (ROS) were reduced in the lung of allergen- challenged mice treated with the SPT inhibitor myriocin (Myr). Based on the preliminary data, I hypothesize that ORMDL3 expression is upregulated specifically in lung epithelial cells during allergic asthma, leading to dramatic increases in sphingolipid metabolites, particularly ceramide. I suggest that this elevation of ceramide contributes to the exacerbation of allergic asthma by inducing apoptosis and/or oxidative stress and that targeting the ORMDL3-ceramide axis will lessen inflammation, airway obstruction, and AHR. To test this hypothesis, in Aim 1, I will examine the mechanisms by which ceramide elevation contributes to asthma exacerbation. In Aim 2, I will investigate the role of global or cell autonomous ORMDL3 overexpression on formation of ceramide and their functions in asthma exacerbation. My proposal will enhance understanding of the pathological roles of ORMDL3 and ceramide in allergic asthma, link enhanced ceramide levels to apoptosis or oxidative stress and susceptibility of asthma, and may pave the way for potential new therapeutic avenues for asthma.