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

人类肥大细胞特异性 Mas 相关基因 X2 (MrgX2) 在过敏反应和哮喘中的作用

• 批准号: 8707142
• 负责人: Hydar Ali
• 金额: $ 20万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707142
• 关键词: Affect; Affinity; Allergens; Allergic; Allergic Disease; American; Anaphylaxis; Animal Model; Asthma; Atherosclerosis; Autoimmune Diseases; Biological Models; Bone Marrow; Bronchoalveolar Lavage; Bronchoconstriction; Bulla; CD34 gene; Cell physiology; Cells; Chymase; Complement; Complement 3a; Complement 5a; Cutaneous; Cytoplasmic Granules; DEFB1 gene; Defensins; Development; Disease; Dorsal; Drug or chemical Tissue Distribution; Ectopic Expression; Epithelial Cells; Experimental Models; Extrinsic asthma; Figs - dietary; Future; G-Protein-Coupled Receptors; Ganglia; Genes; Genetic Polymorphism; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Health Care Costs; Hematopoietic stem cells; Human; Human Development; IgE; IgE Receptors; Immune; Immune system; In Vitro; Inflammatory; Interleukin 2 Receptor; Interleukin-3; Knockout Mice; Laboratories; Left; Ligands; Lung; Lung Inflammation; Malignant Neoplasms; Mediating; Modeling; Mus; Natural Immunity; Nerve Endings; Neuropeptides; Pathogenesis; Patients; Peptide Hydrolases; Peptide Signal Sequences; Peptides; Periodontal Diseases; Phosphorylation; Play; Production; Psoriasis; Regulation; Retroviridae; Rheumatoid Arthritis; Role; Secretory Vesicles; Signal Transduction; Skin; Slice; Substance P; Testing; Transplantation; Tryptase; airway hyperresponsiveness; allergic response; anti-IgE; antimicrobial peptide; base; cathelicidin; cortistatin; crosslink; gain of function; in vivo; in vivo Model; mast cell; mouse model; mutant; neuropeptide FF; novel; novel strategies; novel therapeutic intervention; public health relevance; receptor; receptor expression; reconstitution; response; tool

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 (Fc?RI) 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 ?-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.

描述（由申请人提供）：肥大细胞是多功能免疫细胞，在许多过敏性和炎症性疾病（包括过敏反应和哮喘）中发挥重要作用。高亲和力IgE受体（Fc？RI）导致产生神经肽如NP-FF，其是称为Mas相关基因X2（MrgX 2）的新型G蛋白偶联受体（GPCR）的配体。在人类免疫细胞中，MrgX 2仅在肥大细胞中表达。MrgX 2的一个独特特征是它被抗菌肽（AMP）激活，如cathelicidin、LL-37、人？由肥大细胞、肺上皮细胞和神经末梢产生的防御素和神经肽（NP）P物质和NP-FF。因此，我们假设人类肥大细胞中表达的MrgX 2有助于过敏反应和哮喘的发病机制。然而，MrgX 2在小鼠中不表达，并且许多通过MrgX 2诱导人肥大细胞脱粒的肽不激活鼠肥大细胞。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MrgX 2的体内小鼠模型。 在目标#1中，我们将用表达人MrgX 2和“功能获得”磷酸化缺陷突变体（ST-MrgX 2）的鼠骨髓源性肥大细胞（BMMC）重建Wsh/Wsh肥大细胞缺陷小鼠。在目标#2中，我们将人CD 34+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中，以开发在体内表达人肥大细胞中的MrgX 2的小鼠（人源化小鼠）。这两种小鼠模型将用于确定MrgX 2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靶点，这些疾病影响着数百万美国人，每年的医疗保健费用高达数十亿美元。此外，这两个模型系统的开发将为未来的研究提供新的工具，以确定人肥大细胞MrgX 2对其他炎症和自身免疫疾病的作用，如类风湿性关节炎、银屑病、动脉粥样硬化、皮肤起泡疾病、癌症和牙周病，其中肥大细胞参与其中.