Critical role for Solute Carrier Proteins (SLCs) for mast cell function

项目总结/摘要 肥大细胞已被认为是IgE依赖性过敏性炎症的关键效应细胞。具体地说， 研究表明肥大细胞的失调扩增和/或活化具有有害的 过敏性疾病的后果。这些研究强调迫切需要治疗方法，以靶向 肥大细胞特异性和安全性。为此，我们进行了一项研究，以全面表征 肥大细胞表面蛋白库，以进一步了解肥大细胞如何能够抑制信号产生的， 在体内平衡和疾病中影响肥大细胞功能的复杂环境。这项研究表明， 肥大细胞表达大量来自溶质载体蛋白（SLC）家族的转运蛋白。整体 该提案的目的是检验SLC转运蛋白在肥大细胞功能中起关键作用的假设， 可以有针对性地降低肥大细胞相关疾病的严重程度。 我们的数据表明，从新的SLC库，肥大细胞表达高水平的CD 98重链 （CD98hc）。重要的是，我们的数据表明，CD 98 hc显着有助于颗粒稳态和储存 肥大细胞预先形成的介质阻碍肥大细胞释放大量这些介质的能力 在激活时。此外，我们发现CD 98 hc在肥大细胞增殖和粘附中起重要作用， 细胞外基质成分。此外，我们获得的证据表明，药理学靶向 CD 98 hc可损害人肥大细胞功能。基于这些观察，我们假设CD 98 hc和 SLC转运蛋白家族在肥大细胞稳态健康和疾病中起重要作用。目标1： 将确定CD 98 hc促进肥大细胞功能的机制。在目标2中，我们将评估 CD 98 hc对过敏性气道炎症中肥大细胞功能的影响此外，我们还将研究 抗CD 98抗体对人原发性肥大细胞功能和过敏性气道炎症的影响。在目标3中， 将使用靶向CRISPR/Cas9文库来鉴定影响人类原发性肥大细胞功能的SLC转运蛋白。 细胞 总之，我们的研究有可能揭示SLC转运蛋白在肥大细胞中的新的生物学作用。 功能最后，这些研究将为未来的项目奠定基础，这些项目旨在探索 靶向SLC转运蛋白调节肥大细胞发挥积极作用的疾病的治疗潜力。

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.