The long-term goal of this initiative is the interrogation of a novel mechanism of lung disease initiation and progression as relates to ecigarette (E-Cig) use. We have found that the flavor constituents of many e-liquid (the actual product consumed/vaped by the E-Cig user, which is composed of a propylene glycol (PG)/vegetable glycerin(VG) vehicle, any number of added flavoring constituents and +/- nicotine), beyond nicotine itself, cause cytosolic Ca2+ responses. Additionally, a number (>25) of Ca2+ homeostasis and signaling proteins, including the endoplasmic reticulum Ca2+ sensor STIM1 (stromal interacting molecule-1), are known to be upregulated due to E-Cig, but NOT traditional cigarette, use. As a sensor for the activation of store-operated Ca2+ entry (SOCE), STIM1 is a crucial regulator of Ca2+ homeostasis. Ca2+ itself serves as a universal second messenger that not only controls apoptosis but also influences cell division/growth and gene expression. Furthermore, abnormal Ca2+ homeostasis has been linked to several ailments, including airway inflammation, chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases and lung cancer. Growing evidence suggests that the molecular components of SOCE (STIM1 and the Ca2+ channels that it regulates) play a crucial role in pulmonary disease initiation and progression, indicating that SOCE inhibition is potentially therapeutic. Based upon the available information laid out here, might E-Cig use lead to more aggressive/severe (in comparison to the use of traditional cigarettes) lung disease in the future? This question cannot currently be answered since E-Cigs have only recently been available to the population at large (~10 yrs). Because these products are so new, relatively little is known about their physicochemical properties. Hence, the goals of the current proposal are to (Aim 1) demonstrate STIM1 protein upregulation as a result of E-Cig exposure using a lung epithelial cell line (CALU-3) and to assess Ca2+ regulation/dysregulation in our cell line model (Aim 2). Completion of the proposed Aims will ultimately shed light on the possible health implications of new and emerging tobacco products (such as E-Cigs), provide mechanistic detail on the progression of lung disease in smokers vs. E-Cig users and deliver valuable data on a promising new therapeutic target, STIM1.