MCEMP1 is an adaptor for KIT receptor for mast cell proliferation

项目摘要/摘要： 肥大细胞表达的膜蛋白1(MCEMP1)是一种高表达的跨膜蛋白。 驻肺的肥大细胞。有趣的是，MCEMP1是几种炎症性肺中最重要的诱导基因之一 包括哮喘在内的疾病。事实上，哮喘急性发作期患者MCEMP1的表达较高 高于哮喘恢复期患者。然而，MCEMP1在肥大细胞中的细胞功能和一种病理 MCEMP1在哮喘中的作用完全不清楚。在初步研究中，我发现MCEMP1相互作用 肥大细胞表面有KIT受体。而免疫球蛋白E-FcεRI复合体激活肥大 诱导脱颗粒的细胞，试剂盒表面受体及其配体干细胞因子(SCF)在 肥大细胞的增殖。在干细胞因子刺激下，Mcemp1-/-小鼠的腹膜肥大细胞减少 与野生型小鼠相比，它们的增殖能力更强。此外，SCF介导的肺肥大细胞的体内扩增 Mcemp1-/-小鼠的细胞显著减少。重要的是，Mcemp1-/-小鼠表现出肺减少 哮喘模型中的炎症反应。基于这些，我假设MCEMP1是KIT的关键适配器 促进干细胞因子介导的肥大细胞增殖并参与哮喘的受体信号转导 病情恶化。在此，我试图解决以下问题：(I)MCEMP1在干细胞因子诱导的肥大细胞中的细胞作用 通过增强KIT受体信号进行扩张。(Ii)MCEMP1介导的肥大细胞的病理作用 严重哮喘进展中的扩张性。(Iii)最后，我将制定治疗方法，以抑制 MCEMP1在哮喘中的病理作用总而言之，这项研究不仅将定义病毒的病理生物学作用 MCEMP1在肥大细胞增殖和哮喘进展中的作用，也为新的治疗方法提供了新的见解 哮喘的靶子。该奖项将支持肥大细胞增殖的新分子机制和一个重要的 哮喘领域的机械性发现。

Project Summary/Abstract: Mast Cell Expressed Membrane Protein 1 (MCEMP1) is a transmembrane protein highly expressed in lung-resident mast cells. Interestingly, MCEMP1 is one of the top inducible genes in several inflammatory lung diseases including asthma. Indeed, asthma patients at exacerbation stage show higher expression of MCEMP1 than asthma patients at recovery stage. However, a cellular function of MCEMP1 in mast cells and a pathological role of MCEMP1 in asthma are entirely unknown. In preliminary study, I discovered that MCEMP1 interacted with KIT receptor on the surface of mast cells. While an immunoglobulin E (IgE)–FcεRI complex activates mast cells to induce degranulation, KIT surface receptor and its ligand stem cell factor (SCF) are critical for the proliferation of mast cells. Upon SCF stimulation, peritoneal mast cells from Mcemp1–/– mice showed decreased proliferation compared to those from wild-type mice. In addition, SCF-mediated in vivo expansion of lung mast cells was significantly reduced in Mcemp1–/– mice. Importantly, Mcemp1–/– mice showed reduced lung inflammation in asthma model. Based on these, I hypothesize that MCEMP1 is a critical adaptor for KIT receptor signaling that promotes SCF-mediated mast cell proliferation and contributes to asthma exacerbation. Herein, I seek to address the following: (i) a cellular role of MCEMP1 in SCF-induced mast cell expansion by potentiating KIT receptor signaling. (ii) a pathological role of MCEMP1-mediated mast cell expansion in the progression of severe asthma. (iii) Lastly, I will develop therapeutic approach to inhibit the pathologic function of MCEMP1 in asthma. Collectively, this study will not only define the pathobiological role of MCEMP1 in mast cell expansion and asthma progression, but also provide novel insight into a new therapeutic target for asthma. This award will support a new molecular mechanism of mast cell proliferation and an important mechanistic finding in the field of asthma.