PROJECT SUMMARY/ABSTRACT Mast cells have been recognized as key effector cells in IgE-dependent allergic inflammation. Specifically, studies have shown that a dysregulated expansion and/or activation of mast cells have detrimental consequences in allergic disease. These studies highlight the urgent need for therapeutic approaches to target mast cells specifically and safely. For this purpose, we conducted a study to comprehensively characterize the mast cell surface protein repertoire to further understand how mast cells can transduce signals generated in a complex environment that influences mast cell function in homeostasis and disease. This study revealed that that mast cells express a large number of transporters from the Solute Carrier Protein (SLC) family. The overall goal of this proposal is to test the hypothesis that SLC transporters play a critical role in mast cell function and can be targeted to reduce the severity of mast cell-associated diseases. Our data indicate that from the novel pool of SLCs, mast cells express high levels of the heavy chain of CD98 (CD98hc). Importantly, our data shows that CD98hc significantly contributes to granule homeostasis and storage of mast cell preformed mediators hindering mast cell ability to release significant amounts of these mediators upon activation. Moreover, we found that CD98hc plays a significant role in mast cell proliferation and adhesion to extracellular matrix components. Furthermore, we obtained evidence that pharmacological targeting of CD98hc can impair human mast cell functions. Based on these observations, we hypothesize that CD98hc and the SLC family of transporters play an important role in mast cell homeostasis health and disease. In Aim 1, we will determine the mechanisms by which CD98hc contribute to mast cell function. In Aim 2, we will assess CD98hc contribution to mast cell function in allergic airway inflammation. Moreover, we will examine the effects of an anti-CD98 antibody on human primary mast cell function and allergic airway inflammation. In Aim 3, we will use a targeted CRISPR/Cas9 library to identify SLC transporters impacting function in human primary mast cells. Together, our studies have the potential to uncover novel biological roles for SLC transporters in mast cell function. Finally, these studies will lay the groundwork for future projects that are aimed at exploring the therapeutic potential of targeting SLC transporters to modulate disorders in which mast cells play an active role.