Molecular network regulating dendritic cell differentiation in cancer

树突状细胞（DC）是最有效的抗原呈递细胞（APC），在免疫应答中起关键作用。 产生针对细菌和病毒病原体、肿瘤抗原的免疫应答， 与自身免疫异常的发展有关属于单核/巨噬细胞 细胞的髓系和它们的功能取决于它们的分化和成熟状态。 DC在骨髓中发育。然而，调控骨中DC分化的机制 涉及细胞因子和细胞结合分子的复杂网络的骨髓微环境仍然存在 大部分未知。我们已经积累了本申请中提供的数据，证明DC 分化由骨髓基质通过Notch和Wnt途径之间的合作来调节。 我们提出了一个新的模型，在骨髓和外周血中的DC分化的空间调节 受Notch配体的性质和由Notch产生的Wnt的量调节的淋巴组织 相邻的细胞DC分化异常是肿瘤免疫缺陷的标志之一。是 被认为是肿瘤逃逸的主要机制之一。在初步实验中， 证明了来自荷瘤小鼠的HPC中的Notch和Wnt信号传导被显著抑制。 这与DC分化的抑制密切相关。我们建议下调 这些途径可能是癌症中异常DC分化的原因。这个项目的总体目标是 建议是确定这些异常的机制和潜在的方法， 纠正一下为了实现这些目标，我们提出了三个具体目标： 具体目标1。Wnt信号通路在DC分化和功能中的作用 具体目标2。Notch和Wnt信号在DC调控中的协同作用研究 分化 具体目标3。Wnt和Notch信号在DC异常分化中的作用 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