Molecular network regulating dendritic cell differentiation in cancer

描述（由申请人提供）：树突状细胞（DC）是最有效的抗原呈递细胞（APC），在产生针对细菌和病毒病原体、肿瘤抗原的免疫应答中起关键作用，并参与自身免疫异常的发生。它们属于单核细胞/巨噬细胞髓系细胞，其功能取决于其分化和成熟的状态。DC在骨髓中发育。然而，骨髓微环境中涉及细胞因子和细胞结合分子的复杂网络的DC分化的调控机制在很大程度上仍然未知。我们已经积累了本申请中提供的数据，证明DC分化是通过Notch和Wnt途径之间的合作由骨髓基质调节的。我们提出了一种新的模型的空间调控的DC分化的骨髓和外周淋巴组织的Notch配体的性质和相邻细胞产生的Wnt的量进行调节。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HPC从荷瘤小鼠显着抑制。这与DC分化的抑制密切相关。我们认为这些通路的下调可能是导致癌症中DC分化异常的原因。本提案的总体目标是确定这些异常的机制和纠正这些异常的潜在方法。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。 目标2. Notch和Wnt信号在DC分化调控中的协同作用研究 具体目标3。研究Wnt和Notch信号在癌症中DC分化和功能异常中的作用。 公共卫生相关性：拟开展的研究将探讨Notch和Wnt信号在骨髓微环境中调控DC分化的新机制。我们将测试新的假设，Notch和Wnt途径之间的合作提供了在生理条件下的DC分化的空间调节，这些途径中的缺陷在癌症中的异常树突状细胞分化中起着关键作用。

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.