Regulation of FcÎµRI function by the MS4A gene cluster

MS4A 基因簇对 FcàμRI 功能的调节

基本信息

批准号：
10237296
负责人：
Glenn Paul Cruse
金额：
$ 37.55万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237296
关键词：
11q12 Adult Affect Affinity Allergic Allergic Disease Alzheimer&apos s Disease Amplifiers Asthma Atopic Dermatitis B-Cell Antigen Receptor B-Lymphocytes Biology C-terminal Cell physiology Cells Characteristics Child Chronic Complex Data Development Diagnosis Disease Epigenetic Process Evolution Exhibits Family Food Hypersensitivity Gene Cluster Gene Expression Gene Family Gene Targeting Genes Genetic Histamine Human Hypersensitivity ITAM IgE IgE Receptors Immune Immune response Individual Inflammation Inflammatory Inflammatory Response Inherited Leukotrienes Link Lung MS4A1 gene Mediating Mediator of activation protein Membrane Membrane Microdomains Oligonucleotides PLC gamma1 Pathway interactions Peptide Hydrolases Phenotype Play Predisposition Prevalence Prostaglandins Protein Family Protein Isoforms Proteins Proto-Oncogene Protein c-kit RNA Splicing Receptor Signaling Regulation Role Sequence Homology Serotonin Signal Transduction Structure of parenchyma of lung Surface Techniques Testing Therapeutic Tissue-Specific Gene Expression asthmatic base cytokine genetic linkage analysis genetic manipulation genome wide association study genomic locus individual patient innovation mast cell new therapeutic target novel novel therapeutics protein protein interaction receptor recruit response synergism targeted treatment trafficking treatment strategy

项目摘要

Project summary Allergic diseases such as asthma, atopic dermatitis and food allergies collectively affect 30-40% of adults and children in the U.S. and their prevalence is increasing. Current treatment strategies generally rely upon either neutralizing individual mediators and/or dampening the immune response. However, targeting single mediators in an inflammatory response only removes a fraction of the inflammatory “pool” of mediators and effective novel therapeutics that directly and specifically target inflammatory mast cells is an unmet need. All allergic diseases share a common feature of altered mast cell phenotype resulting in chronic hypersecretion of proinflammatory mast cell mediators such as histamine, serotonin, leukotrienes, prostaglandins, proteases and cytokines. It is likely that inherited genetic characteristics and environmental/epigenetic alterations play important roles in development of this allergic mast cell phenotype. Interestingly, human linkage analysis has identified that the gene loci 11q12-q13 are strongly linked to allergy and asthma susceptibility. The Membrane Spanning (MS)4A gene cluster encodes a family of at least 16 genes in humans that are expressed in immune cells. Current evidence suggests a link between the MS4A family and diseases associated with inflammation. The entire MS4A gene cluster lies within 11q12-q13, suggesting a potential linkage to allergy. In this application, we propose that the MS4A gene cluster plays a critical role in the development of a hyper- responsive mast cell phenotype. Currently, only two of these genes have been studied in detail and both play important roles in immune cell signaling and function. In this study, we will establish the roles of the MS4A gene cluster in human mast cell function and identify MS4A proteins as novel regulators of FcεRI trafficking and signaling that define human mast cell function and responsiveness to IgE signals in mast cells from non-diseased and asthmatic lung. In addition to novel mechanisms that regulate mast cell function, these proteins could represent new drug targets for asthma and other allergic diseases.

项目概要哮喘、特应性皮炎和食物过敏等过敏性疾病总共影响 30-40% 的成年人和目前的治疗策略通常依赖于美国儿童中的任何一种。中和单个介质和/或抑制免疫反应然而，针对单个介质。在炎症反应中，仅去除炎症介质“池”的一小部分，并且有效的新型药物直接、特异性针对炎症肥大细胞的治疗方法是所有过敏性疾病的未满足需求。具有肥大细胞表型的共同特征，导致促炎性物质慢性分泌过多肥大细胞介质，例如组胺、血清素、白三烯、前列腺素、蛋白酶和细胞因子。遗传特征和环境/表观遗传改变很可能在这种过敏性肥大细胞表型的发展。基因位点 11q12-q13 与过敏和哮喘易感性密切相关。跨膜 (MS)4A 基因簇编码人类中至少 16 个基因的家族，这些基因目前的证据表明 MS4A 家族与相关疾病之间存在联系。整个 MS4A 基因簇位于 11q12-q13 内，表明与过敏存在潜在联系。在此应用中，我们提出 MS4A 基因簇在超级细胞的发育中发挥着关键作用。目前，只有其中两个基因得到了详细研究，并且都发挥作用。在免疫细胞信号传导和功能中的重要作用在本研究中，我们将确定 MS4A 基因的作用。簇在人类肥大细胞功能中的作用，并将 MS4A 蛋白鉴定为 FcεRI 运输的新调节因子定义人类肥大细胞功能和对非疾病肥大细胞中 IgE 信号的反应的信号传导除了调节肥大细胞功能的新机制外，这些蛋白质还可以治疗哮喘肺。哮喘和其他过敏性疾病的新药物靶点。