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多种组织巨噬细胞（MP）、树突状细胞（DC）和破骨细胞（OC）。分化的关键调节因子是维甲酸和维生素D3的核受体、脂多糖介导的激酶介导的信号转导、粘附、(G)MCSF和tnf相关的信号系统，如TRANCE/RANK。后者涉及NFkB激活，对OC和DC的分化和功能至关重要。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，其功能依赖于硒半胱氨酸的结合，由相应mRNA的3'调控发夹结构介导。巨噬细胞表达谷胱甘肽过氧化物酶（GPx）和TrxR。巨噬细胞的激活伴随着氧化爆发，由酶复合物NADPH氧化酶介导。本项目旨在阐明GPxs和TrxRs在以下方面的贡献：1)吞噬过程中氧化爆发的比较化；2)通过诱导TrxR过表达和敲除nfkb介导的MP和DC分化和反应性的信号转导；3)通过TrxR过表达和敲除调节分化、吞噬和感染及其在感染、自身免疫和代谢性骨病中的可能相关性。

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.