Regulation of antibody production by the MSK-CREB pathway

抗体的产生是感染应答和有效疫苗接种应答的关键组成部分。然而，它必须小心控制，因为与自身成分反应的抗体的不必要的产生导致自身免疫性疾病的发展。抗体是由B细胞产生的，每个B细胞都具有产生针对特定抗原的抗体的潜力。抗体生产是一个复杂的过程，需要几个步骤。首先，抗原必须被幼稚B细胞识别。在此之后，B细胞将增殖并改变它们产生的抗体类别（或同种型）的类型，以使其适应抗原或感染的类型。同时，它们将增加抗体对抗原的亲和力。这是通过两个过程实现的;类别转换重组（CSR），其改变产生的同种型，和体细胞重组，其允许产生对抗原的高亲和力抗体。这些过程中的缺陷已在常见变异性免疫缺陷等病理学中得到鉴定。了解CSR的分子机制也可能有助于通过促进抗原特异性抗体的产生来创造更好的疫苗。本项目将研究细胞内信号机制如何控制这一过程。具体来说，它将集中在两种酶，MSK 1/2，我们已经发现在初步研究中发挥重要作用的企业社会责任。为了进一步研究这些酶的重要性，在该项目中，我们将重点关注MSK 1/2及其转录因子底物CREB，以及激活它们的上游途径。将使用MSK 1/2的敲除小鼠和CREB的S133 A敲入小鼠进行CSR和体细胞超突变的体内和离体研究。该项目将利用体内研究的组合来观察免疫反应和蛋白质组学，以观察细胞中蛋白质的变化。因此，培训将提供体内生理学以及质谱和结果的生物信息学分析。问题：1.解释跨学科的接口：蛋白质组数据分析将需要生物信息学技能以及基础生物学知识。2.项目是否需要大量的定量技能？是的3.项目是否需要大量的整体生物生理学技能？是的

The production of antibodies is a critical component of the response to infection and for effective vaccination responses. It must however be carefully controlled as the unwanted production of antibodies that react with self-components results in the development of autoimmune diseases. Antibodies are produced by B cells and each B cell has the potential to produce an antibody against a specific antigen. Antibody production is a complex process requiring several steps. First, antigen must be recognised by a naïve B cell. Following this, the B cells will proliferate and change the type of antibody class (or isotype) they produce to tailor it to the type of antigen or infection. At the same time they will increase the affinity of the antibody for the antigen. This is achieved via two processes; class switch recombination (CSR), which changes the isotype produced, and somatic recombination, which allows the generation of high affinity antibodies to the antigen. Defects in these processes have been identified in pathologies such as Common Variable Immune Deficiency. Understanding the molecular mechanism of CSR could also potentially contribute to the creation of better vaccines via boosting antigen specific antibody production. This project will look at how intracellular signalling mechanisms control this process. Specifically it will focus of on two enzymes, MSK1/2, that we have found in preliminary studies to play an important role in CSR. To further investigate the importance of these enzymes, in the project we will focus on MSK1/2 and their transcription factor substrate CREB, as well as the upstream pathways that activate them. Knockout mice for MSK1/2 and S133A knockin mice for CREB will be utilized for both in vivo and ex vivo studies of CSR and somatic hypermutation. The project will make use of a combination of in vivo studies to look a response to immunisation and proteomics to look at the changes in proteins with in the cell. Training will therefore be provided in vivo physiology as well as mass spectrometry and the bioinformatics analysis of the results.Questions:1.Explain interdisciplinary interface: Analysis of proteomic data will require both bioinformatic skills as well as knowledge of basic biology.2.Does project require significant amount of quantitative skills? YES3.Does project require significant amount of whole organism physiology skills? YES