Molecular network regulating dendritic cell differentiation in cancer

调节癌症树突状细胞分化的分子网络

• 批准号: 8658930
• 负责人: Dmitry I Gabrilovich
• 金额: $ 31.5万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658930
• 关键词: Antigen-Presenting Cells; Autoimmune Process; Binding; Bone Marrow; Cell Differentiation process; Cell Lineage; Cells; Complex; Cytokine Network Pathway; Data; Defect; Dendritic Cells; Development; Down-Regulation; Generations; Goals; Immune response; Investigation; Ligands; Lymphoid Tissue; Malignant Neoplasms; Modeling; Molecular; Mus; Myelogenous; Nature; Pathway interactions; Peripheral; Physiological; Play; Regulation; Research; Role; Signal Transduction; Testing; Tumor Antigens; Tumor Escape; Viral; macrophage; monocyte; notch protein; novel; pathogen; research study; tumor

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

树突状细胞（DC）是最有效的抗原呈递细胞（APC），在 针对细菌和病毒病原体，肿瘤抗原的免疫反应产生，并且是 参与自身免疫异常的发展。它们属于单核细胞/巨噬细胞 细胞及其功能的髓样谱系取决于它们的分化和成熟的状态。 DC在骨髓中开发。但是，控制骨骼DC分化的​​机制 骨髓微环境涉及复杂的细胞因子和细胞结合分子的网络 在很大程度上未知。我们在本应用程序中累积了数据，​​证明了DC 骨髓基质通过Notch和Wnt途径之间的合作来调节分化。 我们提出了一个新型的骨髓和周围DC分化的​​空间调节模型 受缺口配体的性质和由淋巴组织和由 相邻细胞。异常DC分化是癌症免疫缺陷的标志之一。这是 被认为是肿瘤逃生的主要机制之一。在初步实验中，我们有 证明来自耐肿瘤小鼠的HPC中的Notch和Wnt信号被显着抑制。 这与DC分化的​​抑制密切相关。我们建议下调 这些途径可能导致癌症异常的直流分化。总体目标 建议是确定这些异常的机制和潜在方法 更正。为了实现这些目标，我们提出了三个具体目标： 特定目的1。调查Wnt信号在DC分化和功能中的作用 具体目的2。在调节DC调控Notch和Wnt信号之间的合作研究 分化 特定目的3。调查Wnt和Notch信号在异常DC分化中的作用 和癌症的功能