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

• 批准号: 10537469
• 负责人: Richard Goff James
• 金额: $ 52.12万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/10537469
• 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; Lead; Location; Lung; Mediating; Mediator of activation protein; Membrane Proteins; Modeling; Morphology; Mus; Peripheral Blood Mononuclear Cell; Pharmacology; Play; Population; Protein Family; Proteins; Publishing; Pyroglyphidae; Reporting; Role; Severities; Signal Transduction; Testing; Therapeutic; airway hyperresponsiveness; allergic airway inflammation; base; granule cell; immunopathology; in vivo; mast cell; mouse model; novel; reconstitution; response; solute; therapeutic development

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.

项目摘要/摘要 肥大细胞被认为是IgE依赖性变态反应性炎症的关键效应细胞。具体来说， 研究表明，肥大细胞的失调扩增和/或激活是有害的 过敏性疾病的后果。这些研究突出表明，迫切需要治疗方法来靶向 特定和安全的肥大细胞。为此，我们进行了一项研究，以全面表征 肥大细胞表面蛋白图谱，以进一步了解肥大细胞如何转导在 在动态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， 肥大细胞表达大量溶质载体蛋白(SLC)家族的转运蛋白。整体而言 这项提议的目标是检验SLC转运蛋白在肥大细胞功能和 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，在新的SLC池中，肥大细胞表达高水平的CD98重链 (CD98hc)。重要的是，我们的数据显示，CD98hc显著促进了颗粒的动态平衡和储存。 肥大细胞预制的介质阻碍了肥大细胞释放大量这些介质的能力 在激活时。此外，我们还发现CD98hc在肥大细胞的增殖和黏附中起着重要的作用。 细胞外基质成分。此外，我们还获得了药物靶向性的证据 CD98hc可损害人的肥大细胞功能。基于这些观察，我们假设CD98hc和 SLC转运蛋白家族在肥大细胞动态平衡、健康和疾病中发挥着重要作用。在目标1中，我们 将决定CD98hc促进肥大细胞功能的机制。在目标2中，我们将评估 CD98hc在过敏性呼吸道炎症中对肥大细胞功能的影响。此外，我们还将检查这些影响 抗CD98抗体对人原代肥大细胞功能和过敏性呼吸道炎症的影响。在目标3中，我们 将使用靶向CRISPR/Cas9文库来确定影响人类初级肥大功能的SLC转运体 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转运体调节肥大细胞发挥积极作用的疾病的治疗潜力。