TLR-induzierte Signalwege bei der Differenzierung und Aktivierung humaner mononukleärer Phagozyten

髓系的效应细胞（单核细胞、巨噬细胞、髓系树突状细胞、粒细胞）是抵御微生物挑战的第一道防线。通过有限数量的模式识别受体，包括最近发现的toll样受体（TLR）家族，它们识别存在于许多病原体中但不存在于宿主组织中的微生物结构，并以细胞类型特异性的方式对微生物感染作出反应。我们项目的主要目的是研究TLR信号通路在人原代先天免疫细胞中的作用，这一研究迄今很少。我们建议建立一种基于外周血干细胞的分化模型，这种干细胞被逆转录病毒构建物转导，表达TLR信号通路的显性阴性形式，随后在体外分化为成熟的髓细胞类型。这种方法应该允许研究TLR生物学的几个重要方面。其中包括确定特定微生物模式使用的信号通路，或tlr诱导的信号通路在人髓细胞分化和激活过程中的作用（例如树突状细胞的成熟，树突状细胞是先天免疫和适应性免疫之间的重要联系）。该项目将进一步加深我们对人类先天免疫防御机制的理解，并可能为许多炎症性疾病提供新的治疗策略。

Effector cells of the myeloid lineage (monocytes, macrophages, myeloid dendritic cells, granulocytes) represent a first line of defense against microbial challenges. Through a limited number of pattern recognition receptors, including the recently discovered family of toll-like receptors (TLR) they recognize microbial structures that are present in many pathogens but absent from host tissues and respond to microbial infection in a cell-type specific manner. The main purpose of our project is to investigate TLR signaling pathways in primary human innate immune cells, which have rarely been studied so far. We propose to establish a differentiation model based on peripheral blood stem cells which are transduced with retroviral constructs to express dominant negative forms of TLR signaling pathway components and are subsequently differentiated into mature myeloid cell types in vitro. This approach should allow the investigation of several important aspects of TLR biology. These include among others the identification of signaling pathways used by particular microbial patterns or the role of TLR-induced signaling pathways during differentiation and activation of human myeloid cells (e g the maturation of dendritic cells which represent an important link between innate and adaptive immunity). The proposed project will further our understanding of innate immune defense mechanisms in humans and may lead to new therapeutic strategies for a number of inflammatory diseases.