Regulation of Syk Expression in Human Basophils

人嗜碱性粒细胞中 Syk 表达的调节

• 批准号: 10434940
• 负责人: Donald W MacGlashan
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-19 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434940
• 关键词: Address; Affect; Allergic Reaction; Antibodies; B-Lymphocytes; Basophils; Behavior; Binding; Biological Response Modifier Therapy; Blood; Blood specimen; CD34 gene; Cells; Clinic; Clinical; Consent; Data; Elements; Event; Family; Feedback; Gene Expression; Generations; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Heterogeneity; Histamine Release; Human; Hypersensitivity; IgE; IgE Receptors; Immediate hypersensitivity; Individual; International; Laboratories; Leukocytes; Link; Linkage Disequilibrium; Mediating; Modeling; Observational Study; Organ; Pathway interactions; Patients; Phosphotransferases; Pilot Projects; Population; Promoter Regions; Protein Tyrosine Kinase; Proteins; Reaction; Regulation; Regulatory Pathway; Reporting; Rodent; SNP genotyping; SYK gene; Sampling; Signal Pathway; Signal Transduction; Testing; Tissues; anti-IgE; base; cell type; clinical efficacy; cytokine; mRNA Differential Displays; mast cell; omalizumab; peripheral blood; programs; promoter; receptor; response; transcription factor; transcriptome

Immediate hypersensitivity reactions are dependent on IgE-mediated activation of basophils and mast cells. There are many elements that regulate expression of the response that distribute up and down the cascade of events from the generation of IgE to the tissue end-organ response and the positive and negative feedback loops that link the various elements together. One of the early necessary elements is related to the intrinsic ability of the basophil and mast cell to respond to aggregation of the IgE receptor. It is now apparent that for human basophils, this intrinsic responsiveness primarily relates the expression of one of the early receptor associated kinases, SYK. Several studies have established that SYK activity is likely a rate-limiting step in the IgE- dependent signal transduction cascade and expression levels determine its activity. Studies have also demonstrated that the very low expression levels of SYK in basophils are unique to this leukocyte. Recent studies demonstrate 5 regulatory pathways of SYK expression, two of which have recently been excluded for further consideration as an explanation for the natural heterogeneity of expression in the population. Based on preliminary results, the application proposes to examine one of newly described pathways in greater detail. A large international study established the association of a SNP family in the SYK gene promoter, in 100% linkage disequilibrium, with SYK expression is multiple cell types. In a pilot study we found that the same SNP family strongly associates with the magnitude of IgE-mediated secretion. Aim 1 of the proposal will expand in both size and detail the pilot study observations. Aim 2 will address a question raised by the possible association of genotype with function, the reversal of suppressed SYK expression in patients with omalizumab. Aim 3 will determine which SNP is relevant to SYK gene expression and examine several hypotheses regarding the transcription factors that modulate the effect.

速发型超敏反应依赖于IgE介导的 嗜碱性粒细胞和肥大细胞。有许多因素调节的表达， 在IgE产生的级联反应中上下分布的反应 到组织终末器官反应和正负反馈回路， 各种元素结合在一起。早期的必要因素之一是与 嗜碱性粒细胞和肥大细胞响应IgE聚集的内在能力 受体的现在很明显，对于人类嗜碱性粒细胞来说，这种内在的反应性 主要涉及早期受体相关激酶之一SYK的表达。 几项研究已经确定SYK活性可能是IgE的限速步骤， 依赖的信号转导级联和表达水平决定其活性。 研究还表明，SYK在嗜碱性粒细胞中的表达水平非常低， 是这种白细胞所独有的最近的研究表明SYK的5个调节途径 表达式，其中两个最近被排除在外，作为一个 解释了群体中表达的天然异质性。基于 初步结果，该申请建议检查一个新描述的 路径更详细。一项大型国际研究表明， SYK基因启动子中的SNP家族，与SYK 100%连锁不平衡 表达是多种细胞类型。在一项初步研究中，我们发现同一个SNP家族 与IgE介导的分泌量密切相关。提案的目标1 将扩大试点研究的规模和详细观察结果。目标2将解决 基因型与功能的可能关联所提出的问题， 奥马珠单抗抑制SYK表达。目标3将决定 SNP与SYK基因表达相关，并检查了关于SYK基因表达的几种假设。 调节这种效应的转录因子。