Regulation of Syk Expression in Human Basophils

人嗜碱性粒细胞中 Syk 表达的调节

• 批准号: 10276240
• 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/10276240
• 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.

直接的超敏反应取决于IgE介导的激活 嗜碱性粒细胞和肥大细胞。有许多元素调节 响应将IgE产生的事件级联分配到上下 到组织的末端响应以及链接的正面和负反馈回路 各种元素在一起。早期必要的要素之一与 嗜碱性粒细胞和肥大细胞对IgE聚集的固有能力 受体。现在很明显，对于人类嗜碱性粒细胞，这种内在的响应能力 主要关联了早期受体相关激酶之一Syk的表达。 几项研究表明，SYK活性可能是IgE的限制步骤 依赖信号转导级联和表达水平决定了其活性。 研究还表明，嗜碱性粒细胞中SYK的表达水平非常低 这是该白细胞独有的。最近的研究表明SYK的5个调节途径 表达，其中两个最近被排除在外，以进一步考虑 人口表达自然异质性的解释。基于 初步结果，申请提议检查一个新描述的 途径更详细。一项大型国际研究建立了 SYK基因启动子中的SNP家族，在100％连锁不平衡的情况下与Syk 表达是多种细胞类型。在一项试点研究中，我们发现同一SNP家族 与IgE介导的分泌的大小密切相关。提案的目标1 试验研究观察结果将扩大规模和详细信息。 AIM 2将解决 基因型可能与功能的关联提出的问题， omalizumab患者的SYK表达抑制。 AIM 3将确定哪个 SNP与Syk基因表达有关，并检查了几种关于 调节效果的转录因子。