Molecular network regulating dendritic cell differentiation in cancer

树突状细胞(DC)是最强大的抗原提呈细胞(APC)，在人类免疫缺陷中起重要作用。 产生针对细菌和病毒病原体、肿瘤抗原以及 参与了自身免疫异常的发展。它们属于单核/巨噬细胞。 细胞的髓系谱系及其功能取决于它们的分化和成熟状态。 DC是在骨髓中发育的。然而，DC在骨骼中分化的机制 涉及细胞因子和细胞结合分子复杂网络的骨髓微环境仍然存在 很大程度上是未知的。我们在此应用程序中提供的累积数据表明，DC 分化是由骨髓基质通过Notch和Wnt途径的协同作用来调节的。 我们提出了一个新的骨髓和外周血树突状细胞分化的空间调控模型。 受Notch配体的性质和所产生的Wnt的量调节的淋巴组织 相邻单元格。DC分化异常是肿瘤免疫缺陷的标志之一。它是 被认为是肿瘤逃逸的主要机制之一。在初步实验中，我们有 结果表明，Notch和Wnt信号在荷瘤小鼠的HPC中受到显著抑制。 这与抑制DC分化密切相关。我们建议下调对 这些途径可能是肿瘤中DC分化异常的原因。这个项目的总体目标是 建议是确定这些异常的机制和可能的方法 更正。为了实现这些目标，我们提出了三个具体目标： 具体目的1.研究Wnt信号在DC分化和功能中的作用 具体目的2.研究Notch和Wnt信号在DC调节中的协同作用 分化 具体目的3.研究Wnt和Notch信号在DC分化异常中的作用 以及在癌症中的作用

Dendritic cells (DC) are the most potent antigen presenting cells (APC) and play a critical role in generation of immune responses against bacterial and viral pathogens, tumor antigens, and are involved in the development of autoimmune abnormalities. They belong to monocyte/macrophage myeloid lineage of cells and their function depends on the state of their differentiation and maturation. DCs are developed in bone marrow. However, the mechanisms governing DC differentiation in bone marrow microenvironment involving complex network of cytokines and cell-bound molecules remain largely unknown. We have accumulated data presented in this application demonstrating that DC differentiation is regulated by bone marrow stroma via cooperation between Notch and Wnt pathways. We propose a novel model of spatial regulation of DC differentiation in bone marrow and peripheral lymphoid tissues that is regulated by the nature of Notch ligands and the amount of Wnt produced by adjacent cells. Abnormal DC differentiation is one of hallmarks of immunological defects in cancer. It is considered as one of the major mechanisms of tumor escape. In preliminary experiments we have demonstrated that Notch and Wnt signaling in HPC from tumor-bearing mice is significantly inhibited. This was closely associated with inhibition of DC differentiation. We propose that down-regulation of these pathways could be responsible for abnormal DC differentiation in cancer. The overall goal of this proposal is to identify the mechanisms of these abnormalities and potential approaches to their correction. To achieve these goals we propose three specific aims: Specific Aim 1. Investigation the role of Wnt signaling in DC differentiation and function Specific Aim 2. Study of cooperation between Notch and Wnt signaling in regulation of DC differentiation Specific Aim 3. Investigation the role of Wnt and Notch signaling in abnormal DC differentiation and function in cancer