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MCEMP1 is an adaptor for KIT receptor for mast cell proliferation

MCEMP1 是用于肥大细胞增殖的 KIT 受体的接头

基本信息

批准号：
10214740
负责人：
Youn Jung Choi
金额：
$ 10.18万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214740
关键词：
Accounting Address Adoptive Transfer Allergens Allergic Allergic Disease Allergic Reaction Anaphylaxis Antigens Asthma Attenuated Award Bypass Cell Count Cell Proliferation Cell physiology Cells Chimeric Proteins Complex Dendritic Cells Development Disease Extrinsic asthma Functional disorder Genes ITAM IgE Immunization In Vitro Inflammatory Injections Integral Membrane Protein Intranasal Administration Libraries Ligands Llama Lung Lung Inflammation Lung diseases Mediating Membrane Proteins Molecular Mus Mutagenesis Ovalbumin Pathogenesis Pathologic Pathway interactions Patients Peritoneal Phase Phosphorylation Phosphotransferases Play Production Pyroglyphidae Receptor Signaling Recovery Regulation Role Severities Signal Pathway Signal Transduction Stem Cell Factor Stimulus Surface System Techniques Testing Therapeutic Wild Type Mouse Yeasts airway hyperresponsiveness asthma exacerbation asthma model asthmatic patient base bronchial epithelium cytokine in vivo inflammatory lung disease inhibitor/antagonist insight macrophage mast cell migration monocyte mouse model nanobodies new therapeutic target novel novel therapeutic intervention novel therapeutics receptor recruit single-cell RNA sequencing stem cells therapeutic development

项目摘要

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.

项目概要/摘要：肥大细胞表达膜蛋白1（MCEMP 1）是一种在肥大细胞中高度表达的跨膜蛋白。肺内肥大细胞有趣的是，MCEMP 1是几种炎症性肺组织中最常见的诱导基因之一，包括哮喘在内的疾病。事实上，哮喘患者在急性发作期表现出更高的MCEMP 1表达，哮喘患者在恢复期然而，MCEMP 1在肥大细胞中的细胞功能和病理性的 MCEMP 1在哮喘中的作用完全未知。在初步研究中，我发现MCEMP 1与与肥大细胞表面的KIT受体结合。免疫球蛋白E（IgE）-FcεRI复合物激活肥大细胞，细胞诱导脱粒，KIT表面受体及其配体干细胞因子（SCF）是关键的，肥大细胞增殖。SCF刺激后，Mcemp 1-/-小鼠的腹腔肥大细胞显示减少，与野生型小鼠相比，此外，SCF介导的肺肥大细胞的体内扩增， Mcemp 1-/-小鼠中细胞显著减少。重要的是，Mcemp 1-/-小鼠表现出减少的肺哮喘模型中炎症。基于这些，我假设MCEMP 1是KIT的关键适配器促进SCF介导的肥大细胞增殖并导致哮喘的受体信号传导加重在此，我试图解决以下问题：（i）MCEMP 1在SCF诱导的肥大细胞中的细胞作用通过增强KIT受体信号传导进行扩增。(ii)MCEMP 1介导的肥大细胞的病理作用严重哮喘的进展。(iii)最后，我将开发治疗方法来抑制 MCEMP 1在哮喘中的病理作用总的来说，这项研究不仅将确定的病理生物学作用， MCEMP 1在肥大细胞扩增和哮喘进展中的作用，也为新的治疗方法提供了新的见解。哮喘的目标该奖项将支持肥大细胞增殖的新分子机制和重要的在哮喘领域的机械发现。