Novel functions of polysialic acid in kidney and immune cell development

本提案的目的是阐明聚唾液酸（polySia）在造血干细胞（HSC）发育、造血和维持免疫稳态中的作用。在第一个资助期内，我们将趋化因子CXCL 12鉴定为新型polySia结合蛋白。缺乏多聚唾液酸转移酶ST 8 Sia 4的小鼠的初步分析揭示了表型改变，这让人想起在CXCR 4/CXCL 12信号传导轴缺陷的动物中观察到的变化，包括改变的HSC和免疫稳态以及老年小鼠中自身免疫性疾病狼疮肾炎发展的迹象。在下一个资助期内，我们将研究CXCL 12的结构-功能关系，并与P8项目密切合作，确定参与polySia结合的关键残基。为了了解聚唾液酸化如何促进HSC的发育，我们将在组成性St 8 sia 4敲除小鼠中扩展我们的分析，并使用分离的原代细胞进行功能测定。最后，我们将通过产生B细胞特异性St 8 Sia 4敲除小鼠来补充项目P2和P10在解剖ST 8 Sia 4缺陷对自身免疫的影响方面的努力。一个具体的重点将设置在体液免疫反应和狼疮肾炎的发展B细胞聚唾液酸化的作用。除了与P2、P8和P10紧密互动外，我们还将与P1、P5和P9密切合作，并得到P3和P7的支持。

The aim of this proposal is to unravel the role of polysialic acid (polySia) in the development of hematopoietic stem cells (HSC), hematopoiesis, and the maintenance of immune homeostasis. In the first funding period, we identified the chemokine CXCL12 as novel polySia binding protein. Initial analysis of mice lacking the polysialyltransferase ST8Sia4 revealed phenotypic alterations that are reminiscent to changes seen in animals with defects in the CXCR4/CXCL12 signaling axis, including altered HSC and immune homeostasis and signs for the development of the autoimmune disease Lupus nephritis in aged mice. In the next funding period, we will study structure-function relationships of CXCL12 to define, in close collaboration with project P8, key residues involved in polySia binding. To understand how polysialylation contributes to HSC development, we will extend our analyses in constitutive St8sia4 knockout mice and perform functional assays with isolated primary cells. Finally, we will complement efforts of projects P2 and P10 in dissecting the impact of ST8Sia4-deficiency on autoimmunity by generating B-cell specific St8Sia4 knockout mice. A specific focus will be set on the role of B-cell polysialylation for humoral immune response and the development of Lupus nephritis. Besides tight interactions with P2, P8 and P10, we will closely collaborate with P1, P5 and P9, and will get support from P3 and P7.