Human mast cell-specific Mas-related Gene-X2 (MrgX2) in Anaphylaxis and Asthma

描述（由申请人提供）：肥大细胞是多功能免疫细胞，在包括过敏反应和哮喘在内的许多过敏性和炎症性疾病中发挥重要作用。高亲和ige受体（FcεRI）交联后，肥大细胞的激活导致神经肽如NP-FF的产生，这些神经肽是一种新型G蛋白偶联受体（GPCR）的配体，称为mass相关基因X2 （MrgX2）。在人类免疫细胞中，MrgX2仅在肥大细胞中表达。MrgX2的一个独特之处在于它被肥大细胞、肺上皮细胞和神经末梢产生的抗菌肽（抗菌肽）如cathelicidin、LL-37、人β-防御素和神经肽（神经肽）物质P和NP-FF激活。因此，我们假设在人肥大细胞中表达的MrgX2参与了过敏反应和哮喘的发病机制。然而，MrgX2在小鼠中不表达，许多通过MrgX2诱导人肥大细胞脱颗粒的肽并不激活小鼠肥大细胞。为了验证我们的假设，我们将开发两种在肥大细胞中表达人类MrgX2的体内小鼠模型。在目标#1中，我们将用小鼠骨髓源性肥大细胞（BMMCs）表达人MrgX2和“功能获得”磷酸化缺陷突变体（ST-MrgX2）重建Wsh/Wsh肥大细胞缺陷小鼠。在目标#2中，我们将把人CD34+造血干细胞移植到表达人肥大细胞生长因子的免疫缺陷小鼠体内，培养在体内表达人肥大细胞MrgX2的小鼠（人源化小鼠）。这两种小鼠模型将用于确定MrgX2在体内对ige介导的皮肤过敏反应和肺部炎症/气道高反应性（AHR）的作用。我们相信，如果这个项目的目标得以实现，它可能会为治疗过敏性疾病提供一个新的目标，这些疾病影响数百万美国人，每年花费数十亿美元的医疗保健费用。此外，这两个模型系统的发展将为未来的研究提供新的工具，以确定人类肥大细胞MrgX2在其他炎症和自身免疫性疾病中的作用，如类风湿关节炎、牛皮癣、动脉粥样硬化、皮肤起疱性疾病、癌症和牙周病等肥大细胞相关疾病。

DESCRIPTION (provided by applicant): Mast cells are multifunctional immune cells that play important roles in a number of allergic and inflammatory diseases including anaphylaxis and asthma. Activation of mast cells following cross-linking of high affinity IgE-receptors (FcεRI) leads to the production of neuropeptides such as NP-FF, which are ligands for a novel G protein coupled receptor (GPCR) known as Mas-related Gene X2 (MrgX2). Of the human immune cells, MrgX2 is expressed ONLY in mast cells. A unique feature of MrgX2 is that it is activated by antimicrobial peptides (AMPs) such as the cathelicidin, LL-37, human β-defensins and neuropeptides (NPs) substance P and NP-FF, which are produced by mast cells, lung epithelial cells and nerve endings. We therefore hypothesize that MrgX2 expressed in human mast cells contributes to the pathogenesis of anaphylaxis and asthma. However, MrgX2 is not expressed in mice and many of the peptides that induce degranulation in human mast cells via MrgX2 do not activate murine mast cells. To test our hypothesis, we will develop two in vivo mouse models that express human MrgX2 in mast cells. In aim #1, we will reconstitute Wsh/Wsh mast cell-deficient mice with murine bone marrow-derived mast cells (BMMCs) expressing human MrgX2 and a "gain of function" phosphorylation-deficient mutant ( ST-MrgX2). In aim #2, we will transplant human CD34+ hematopoietic stem cells into immune-deficient mice expressing growth factors for human mast cells to develop mice (humanized mice) that express MrgX2 in human mast cells in vivo. These two mouse models will be used to determine the role of MrgX2 on IgE-mediated cutaneous anaphylaxis and lung inflammation/airway hyperresponsiveness (AHR) in vivo. We believe that if the goals of this project are realized, it may provide a novel target for the treatment of allergic diseases that affect millions of Americans with billions of dollars in annual health care cost. Furthermore, development of these two model systems will provide new tools for future studies to determine the role of a human mast cell MrgX2 on other inflammatory and autoimmune diseases, such as rheumatoid arthritis, psoriasis, atherosclerosis, skin- blistering diseases, cancer and periodontal disease, in which mast cells are implicated.