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.
Allergic asthma is one of the most prevalent airway diseases in industrialized countries, marked by chronic inflammation of the airways, shortness of breath, airway hyperreactivity, and difficult periods of breathing, and over the years, a multitude of asthmatic factors have been unveiled. This proposal is focused on the link of one of these risk factors, ORMDL3, to regulation of the sphingolipid metabolite ceramide and as a consequence, the important role of ceramide in regulation of apoptosis and oxidative stress. Targeting the ceramide axis may potentially be a novel approach to alleviate allergic asthma.
