The impact of selenium and selenoproteins on stem cell based bone regeneration and regulation of celcium metabolism

单核细胞终末分化为各种组织巨噬细胞（MP）、树突状细胞（DC）和破骨细胞（OC）。分化的关键调节因子是视黄酸和维生素D3的核受体、LPS介导的激酶介导的信号转导、粘附、（G）MCSF和TNF相关信号系统（如TRANCE/RANK）。后者涉及NFkB活化，并且对于OC和DC分化和功能是必需的。NFkB活性由硒酶硫氧还蛋白还原酶a（TrxRa）调节。硒蛋白是一组酶，其功能上依赖于由相应mRNA的3 '-调节发夹结构介导的硒代半胱氨酸的掺入。硒酶谷胱甘肽过氧化物酶（GPx）和TrxR在巨噬细胞中表达。巨噬细胞的活化伴随着由酶复合物NADPH氧化酶介导的氧化爆发。该项目旨在阐明GPx和TrxR对I）吞噬作用期间氧化爆发的比较，II）使用诱导型TrxR过表达和敲除的NF κ B介导的MP和DC的分化和反应性的信号转导和III）通过TrxR过表达和敲除的分化、吞噬和感染的调节及其在感染、自身免疫和代谢性骨病中的推定相关性的贡献。

Monocytes terminally differentiate into a variety of tissue macrophages (MP), dendritic cells (DC) and osteoclasts (OC). Key regulators of differentiation are nuclear receptors for retinoic acid and vitamin D3, kinase-mediated signal transduction by LPS, adhesion, (G)MCSF and TNF-related signaling systems like TRANCE/RANK. The latter involves NFkB activation and is essential for OC and DC differentiation and function. NFkB activity is modulated by the selenoenzyme thioredoxin reductase a (TrxRa). Selenoproteins are a group of enzymes which functionally depend on the incorporation of selenocysteine mediated by a 3'- regulatory hairpin structure of the respective mRNA. The selenoenzymes glutathione peroxidases (GPx) and TrxR are expressed in macrophages. Activation of macrophages is accompanied by an oxidative burst, mediated by the enzyme complex NADPH oxidase. This project sets out to elucidate the contribution of GPxs and TrxRs to I) compartimentalization of the oxidative burst during phagocytosis, II) NFkB-mediated signal transduction for differentiation and reactivity of MP and DC using inducible TrxR overexpression and knockout and III) the modulation of differentiation, phagocytosis and infection through TrxR overexpression and knockout and its putative relevance in infection, autoimmunity and metabolic bone diseases.