Modulation of immunological processes by KSRP

KSRP 调节免疫过程

• 批准号: 460054481
• 负责人: Privatdozent Dr. Matthias Bros
• 金额: --
• 依托单位: Hautklinik Mainz
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/460054481?language=en
• 关键词: Modulation; immunological; processes; KSRP

The regulation of the functional activities of immune cells requires dynamic rapid adaption of gene expression. In immortalized cell lines, KSRP (KH-type splicing regulatory protein) was reported to limit mRNA stability of cytokine-encoding mRNAs and to mediate microRNA-155 maturation, known to contribute to immune cell regulation. KSRP limited the half-life of type I interferon-encoding genes, and in agreement KSRP-/- mice displayed higher resistance towards viral infection. Our preliminary work indicated that KSRP affects the functional activity of polymorphonuclear neutrophilic granulocytes (PMN) in terms of migratory activity. Moreover, KSRP-/- CD4+ T cells were characterized by an intrinsic T helper cell type 2 (Th2) bias in response to stimulation as confirmed by RNA-Seq and cytokine measurements. In line, KSRP-/- mice presented a milder course of collagen antibody induced-arthritis (CAIA) known to be caused by myeloid and Th1 cells. Similarly, KSRP-/- mice presented an aggravated course in ovalbumin (OVA)-induced asthma Taken together, our results indicate that KSRP constitutes a yet unknown important regulator of immune responses.Our study is aimed to delineate the role of KSRP for the regulation of innate and adaptive immune responses as a prerequisite to envisage KSRP-focused therapeutic approaches. We want to substantiate our preliminary findings concerning the aggravated course of OVA-associated asthma, and elucidate in detail the relative contribution of T cells, B cells and PMN. We will dissect on molecular level by which mechanisms KSRP inhibits expression of Th2-promoting IL-4 in CD4+ T cells, including the identification of important transcription factors and signalling adaptors. In this context, we will also discriminate direct and indirect KSRP target genes in T cells based on our RNA-Seq results. We will dissect both intrinsic and extrinsic (Th2 help) effects of KSRP deficiency on the immunophenotype and function of B cells concerning the character of humoral immune responses. Furthermore, the reasons for enhanced proliferation of KSRP-deficient CD4+ T cells as well as KSRP-mediated regulatory T cell function will be examined. The functional relevance of KSRP for pathogen killing activity of PMN will be monitored in a model of aspergillosis. Furthermore, we will perform rescue experiments in the asthma disease model to substantiate the suitability of KSRP for immunopharmacological intervention. Mice with a cell type-specific KSRP knockout will be generated to confirm key experiments from asthma studies.

免疫细胞功能活动的调节需要基因表达的动态快速适应。在永生化细胞系中，据报道KSRP（KH型剪接调节蛋白）限制了编码精氨酸的mRNA的mRNA稳定性，并介导已知有助于免疫细胞调节的microRNA-155成熟。KSRP限制了I型干扰素编码基因的半衰期，并且一致地KSRP-/-小鼠显示出对病毒感染的更高抗性。我们的初步工作表明，KSRP影响多形核白细胞（PMN）的迁移活动方面的功能活动。此外，KSRP-/-CD 4 + T细胞的特征在于响应于刺激的固有T辅助细胞2型（Th 2）偏好，如通过RNA-Seq和细胞因子测量所证实的。与此同时，KSRP-/-小鼠出现了较轻的胶原抗体诱导关节炎（CAIA），已知是由骨髓和Th 1细胞引起的。同样，KSRP-/-小鼠在卵清蛋白（OVA）诱导的哮喘中表现出加重的过程。总之，我们的研究结果表明，KSRP构成了一个未知的重要调节免疫应答。我们的研究旨在描述KSRP的先天性和适应性免疫应答的调节作用，作为设想KSRP为重点的治疗方法的先决条件。我们希望证实我们关于OVA相关哮喘加重过程的初步发现，并详细阐明T细胞、B细胞和PMN的相对贡献。我们将在分子水平上剖析KSRP抑制CD 4 + T细胞中Th 2促进IL-4表达的机制，包括鉴定重要的转录因子和信号衔接子。在这种情况下，我们还将根据我们的RNA-Seq结果区分T细胞中的直接和间接KSRP靶基因。我们将剖析内在和外在（Th 2帮助）KSRP缺陷对免疫表型和B细胞功能的影响，有关的体液免疫应答的特点。此外，将检查KSRP缺陷型CD 4 + T细胞增殖增强以及KSRP介导的调节性T细胞功能增强的原因。将在曲霉病模型中监测KSRP与PMN的病原体杀灭活性的功能相关性。此外，我们将在哮喘疾病模型中进行补救实验，以证实KSRP用于免疫药理学干预的适用性。将产生具有细胞类型特异性KSRP敲除的小鼠，以确认哮喘研究的关键实验。