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展。它们属于单核/巨噬细胞髓系细胞，它们的功能取决于它们的分化和成熟状态。树突状细胞在骨髓中发育。然而，在骨髓微环境中控制DC分化的机制涉及细胞因子和细胞结合分子的复杂网络，在很大程度上仍然未知。我们在本应用中积累的数据表明，骨髓基质通过Notch和Wnt通路之间的合作调节DC分化。我们提出了骨髓和外周淋巴组织DC分化的空间调节新模型，该模型受Notch配体的性质和邻近细胞产生的Wnt数量的调节。异常DC分化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，我们已经证明了Notch和Wnt信号在荷瘤小鼠的HPC中被显著抑制。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导致癌症中DC分化异常的原因。本建议的总体目标是确定这些异常的机制和潜在的纠正方法。为实现这些目标，我们提出三个具体目标：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信号在肿瘤DC异常分化和功能中的作用。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。我们将验证Notch和Wnt通路之间的合作在生理条件下为DC分化提供空间调节，并且这些通路的缺陷在癌症中异常树突状细胞分化中起关键作用的新假设。

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.