Molecular network regulating dendritic cell differentiation in cancer

描述(申请人提供)：树突状细胞(DC)是最强大的抗原提呈细胞(APC)，在产生针对细菌和病毒病原体、肿瘤抗原的免疫反应中发挥关键作用，并参与自身免疫异常的发生。它们属于单核/巨噬细胞的髓系细胞，其功能取决于其分化和成熟状态。DC是在骨髓中发育的。然而，在涉及细胞因子和细胞结合分子复杂网络的骨髓微环境中，DC分化的机制仍然很大程度上是未知的。我们在这项应用中积累的数据表明，DC的分化是由骨髓基质通过Notch和Wnt途径之间的合作来调节的。我们提出了一种新的骨髓和外周淋巴组织中DC分化的空间调控模型，该模型由Notch配体的性质和相邻细胞产生的Wnt的数量来调节。DC分化异常是肿瘤免疫缺陷的标志之一。它被认为是肿瘤逃逸的主要机制之一。在初步实验中，我们已经证明Notch和Wnt信号在荷瘤小鼠的HPC中受到显着抑制。这与抑制DC分化密切相关。我们认为，这些通路的下调可能是癌症中DC分化异常的原因。这项提案的总体目标是确定这些异常情况的机制和纠正这些异常情况的可能办法。为了实现这些目标，我们提出了三个具体目标：具体目标1.研究Wnt信号在DC分化和功能特异性中的作用。目的2.研究Notch和Wnt信号在DC分化调控中的协同作用。具体目的3.研究Wnt和Notch信号在肿瘤中DC分化和功能异常中的作用。公共卫生相关性：拟议的研究将通过Notch和Wnt信号研究骨髓微环境中调节DC分化的新机制。我们将测试新的假设，即Notch和Wnt通路之间的合作提供了生理条件下DC分化的空间调节，并且这些通路中的缺陷在癌症中异常的树突状细胞分化中起关键作用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Proposed research will investigate novel mechanism of regulation of DC differentiation in bone marrow microenvironment by Notch and Wnt signaling. We will test novel hypothesis that cooperation between Notch and Wnt pathways provides for spatial regulation of DC differentiation under physiological conditions and that defects in these pathways play a critical role in abnormal dendritic cell differentiation in cancer.