Regulation of Syk Expression in Human Basophils

即刻超敏反应依赖于IgE介导的 嗜碱性粒细胞和肥大细胞。有许多元素可以调节基因的表达 从生成IgE开始沿事件级联上下分布的响应 到组织末端器官反应和连接的正、负反馈环路 各种元素汇聚在一起。早期的必要元素之一与 嗜碱性粒细胞和肥大细胞对IgE聚集的内在反应能力 受体。现在很明显，对于人类嗜碱性粒细胞，这种内在的反应性 主要与早期受体相关的一种激酶--SYK的表达有关。 一些研究已经证实，SYK活性可能是IgE-1的一个限速步骤。 依赖的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的极低表达水平 是这种白细胞所独有的。最近的研究证实了SYK的5条调控途径 表达式，其中两个最近被排除在外，作为 解释了种群中基因表达的自然异质性。基于 初步结果，应用程序建议检查新描述的 更详细的路径。一项大型国际研究确定了一种 SNP家族中的SYK基因启动子，处于100%连锁不平衡状态，与SYK 表达式是多种单元格类型。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 将在规模和细节两方面扩大试点研究的观察结果。Aim 2将针对 由基因与功能的可能关联提出的问题，逆转了 抑制奥马珠单抗患者SYK的表达。目标3将决定 SNP与SYK基因表达相关，并检验了几种关于SYK基因表达的假说 调节这种效应的转录因子。

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.