Project Summary/Abstract: Mast Cell Expressed Membrane Protein 1 (MCEMP1) is a transmembrane protein highly expressed in lung-resident mast cells. Interestingly, MCEMP1 is one of the top inducible genes in several inflammatory lung diseases including asthma. Indeed, asthma patients at exacerbation stage show higher expression of MCEMP1 than asthma patients at recovery stage. However, a cellular function of MCEMP1 in mast cells and a pathological role of MCEMP1 in asthma are entirely unknown. In preliminary study, I discovered that MCEMP1 interacted with KIT receptor on the surface of mast cells. While an immunoglobulin E (IgE)–FcεRI complex activates mast cells to induce degranulation, KIT surface receptor and its ligand stem cell factor (SCF) are critical for the proliferation of mast cells. Upon SCF stimulation, peritoneal mast cells from Mcemp1–/– mice showed decreased proliferation compared to those from wild-type mice. In addition, SCF-mediated in vivo expansion of lung mast cells was significantly reduced in Mcemp1–/– mice. Importantly, Mcemp1–/– mice showed reduced lung inflammation in asthma model. Based on these, I hypothesize that MCEMP1 is a critical adaptor for KIT receptor signaling that promotes SCF-mediated mast cell proliferation and contributes to asthma exacerbation. Herein, I seek to address the following: (i) a cellular role of MCEMP1 in SCF-induced mast cell expansion by potentiating KIT receptor signaling. (ii) a pathological role of MCEMP1-mediated mast cell expansion in the progression of severe asthma. (iii) Lastly, I will develop therapeutic approach to inhibit the pathologic function of MCEMP1 in asthma. Collectively, this study will not only define the pathobiological role of MCEMP1 in mast cell expansion and asthma progression, but also provide novel insight into a new therapeutic target for asthma. This award will support a new molecular mechanism of mast cell proliferation and an important mechanistic finding in the field of asthma.