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

溶质载体蛋白 (SLC) 对肥大细胞功能的关键作用

基本信息

批准号：
10652657
负责人：
Richard Goff James
金额：
$ 75万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-24 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652657
关键词：
Address Adhesions Adjuvant Affinity Allergens Allergic Allergic Disease Allergic inflammation Amino Acids Antibodies Biological Biological Process CRISPR library CRISPR screen Carrier Proteins Cell Adhesion Cell Proliferation Cell Surface Proteins Cell physiology Cells Cellular biology Chimera organism Complex Cytoplasmic Granules Data Disease Dose Effector Cell Environment Extracellular Matrix Future Goals Health Homeostasis Human IgE Immune Impairment Individual Integrin beta Chains Integrins Knowledge Location Lung Mediating Mediator Membrane Proteins Modeling Morphology Mus Peripheral Blood Mononuclear Cell Play Population Proliferating Protein Family Proteins Publishing Pyroglyphidae Reporting Role Severities Signal Transduction Testing Therapeutic airway hyperresponsiveness allergic airway inflammation granule cell immunopathology in vivo mast cell mouse model novel pharmacologic reconstitution response solute therapeutic development

项目摘要

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.

项目概要/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。具体来说，研究表明，肥大细胞的扩张和/或激活失调会产生有害的影响。过敏性疾病的后果。这些研究强调迫切需要针对目标的治疗方法肥大细胞特异性且安全。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转导在影响体内平衡和疾病中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溶质载体蛋白（SLC）家族的转运蛋白。整体该提案的目标是检验 SLC 转运蛋白在肥大细胞功能中发挥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 库中，肥大细胞表达高水平的 CD98 重链 (CD98hc)。重要的是，我们的数据表明 CD98hc 对颗粒稳态和储存有显着贡献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激活后。此外，我们发现CD98hc在肥大细胞增殖和粘附中发挥重要作用细胞外基质成分。此外，我们获得的证据表明，药物靶向 CD98hc 可损害人类肥大细胞功能。基于这些观察，我们假设 CD98hc 和 SLC 转运蛋白家族在肥大细胞稳态健康和疾病中发挥着重要作用。在目标 1 中，我们将确定 CD98hc 促进肥大细胞功能的机制。在目标 2 中，我们将评估 CD98hc 对过敏性气道炎症中肥大细胞功能的贡献。此外，我们将检查效果抗 CD98 抗体对人原代肥大细胞功能和过敏性气道炎症的影响。在目标 3 中，我们将使用靶向 CRISPR/Cas9 文库来识别影响人类初级肥大功能的 SLC 转运蛋白细胞。总之，我们的研究有可能揭示肥大细胞中 SLC 转运蛋白的新生物学作用功能。最后，这些研究将为未来的项目奠定基础，旨在探索靶向 SLC 转运蛋白以调节肥大细胞发挥积极作用的疾病的治疗潜力。