AUTOIMMUNITY TO AND MRNA SPLICING REGULATION BY SWAP

系统性红斑狼疮(SLE)以自身抗体为特征 对抗组成小核核糖核蛋白(SnRNPs)的蛋白质。 SnRNP是剪接体的组成部分，剪接体是剪接的细胞器 非编码区(内含子)从前-信使核糖核酸中脱出，形成成熟信使核糖核酸。在……里面 一般的信使核糖核酸剪接是通过SNRNPs的相互作用严格定义的 前-mRNA上含有顺式元件的SnRNP相关蛋白。在……里面 相比之下，在某些基因中，一个或多个内含子可以拼接成多个 单程票。这一过程被称为替代剪接。研究 到目前为止，已经表明选择性剪接是通过 蛋白质与构成剪接体蛋白和前信使核糖核酸的相互作用。 选择性剪接的调节导致蛋白质的合成 具有不同的功能，因此是调节的重要机制 基因表达。尽管我们知道很多关于基因的信息 另一种是剪接，人们对调节这一过程的基因知之甚少 进程。我们最近发现了一种新的自身抗原(SWAP)，它是 与果蝇基因(su[w/a])同源，该基因调控另一种选择 拼接。SU(w/a)自动调节su(w/a)Pre-RNA和SWAP的剪接 产生类似的选择性剪接的mRNA，这表明交换是 也是一个剪接调节器。SLE患者中抗SNRNPs抗体是 针对靶向SnRNP蛋白的多个表位，因此 可能反映了对这些颗粒的自动免疫过程。我们有 显示交换抗体类似地针对多个 蛋白质上的表位，但在正常和自身免疫中发现 病人。我们的假设是，这些抗体是一个过程的结果 正常的自体免疫。它在细胞内的有限分布 剪接调节因子可能指向正常的SnRNP的细胞来源 免疫接种。 我们建议将对SWAP的功能和自身免疫的研究扩展到SWAP。 SWAP自身抗体产生对T细胞的依赖性。他的年龄是 抗体产生来交换正常人自身抗体的产生。 我们将探讨有关自身免疫和功能的问题。 通过分析SWAP mRNA和蛋白表达的分布。 这将包括对细胞在凋亡过程中的表达进行分析。 和激活的抗原提呈细胞，潜在的细胞事件 与自身免疫反应有关。分子研究将确定 SWAP是否自动调节SWAP Pre-mRNA的剪接，并探索这一点是如何实现的 蛋白质与其他SnRNP蛋白相互作用，调节剪接。这个 将通过创造转基因来探索SWAP的发育效应 老鼠，过度表达一种互换转基因。进一步定义交换拼接的步骤 在生理上重要的替代方案背景下的管制 剪接及其对CD45和bcl-x交替剪接的影响 将对拼接进行研究。

Systemic lupus erythematosus (SLE) is characterized by autoantibodies against proteins that make up small nuclear ribonucleoproteins (snRNPs). snRNPs are components of spliceosomes, cellular organelles that splice non-coding regions (introns) out of pre-mRNA to form mature mRNA. In general mRNA splicing is rigidly defined through interactions of snRNPs and snRNP-associated proteins with (cis) elements on pre-mRNA. In contrast, in some genes one or more introns can be spliced in more than one way. This process is referred to as alternative splicing. Studies to date have indicated that alternative splicing is regulated through protein interactions with constitutive spliceosome proteins and pre-mRNA. Regulation of alternative splicing leads to the synthesis of proteins with different functions and thus is an important mechanism in regulating gene expression. Although much is known about genes that are alternatively spliced, little is known about genes that regulate this process. We have recently identified a new autoantigen (SWAP) that is homologous to a Drosophila gene (su[w/a]) that regulates alternative splicing. su(w/a) autoregulates splicing of su(w/a) pre-RNA and SWAP produces similarly alternatively spliced mRNAs, suggesting that SWAP is also a splicing regulator. Antibodies to snRNPs in SLE patients are directed against multiple epitopes of targeted snRNP proteins, and thus may reflect a process of auto-immunization to these particles. We have shown that SWAP antibodies are similarly directed against multiple epitopes on the protein, but are found in normal as well as autoimmune patients. Our hypothesis is that these antibodies result from a process of normal autoimmunization. The restricted cellular distribution of this splicing regulator may point to a cellular source of normal snRNP immunization. We propose to extend studies of the function of and autoimmunity to SWAP. T-cell dependence of SWAP autoantibody production. The age at which antibody production to SWAP autoantibody production in normal humans. Questions regarding both autoimmunity and function will be explored through analyses of the distribution of SWAP mRNA and protein expression. This will include analyses of expression in cells undergoing apoptosis and activated antigen presenting cells, cellular events potentially associated with autoimmune responses. Molecular studies will determine whether SWAP autoregulates splicing of SWAP pre-mRNA and explore how this protein interacts with other snRNP proteins to regulate splicing. The developmental effects of SWAP will be explored by creating transgenic mice, overexpressing a SWAP transgene. To further define SWAP splicing regulation in the context of physiologically important alternative splicing, its effect on the alternative splicing of CD45 and bcl-x splicing will be studied.