Role of Notch signaling in the Differentiation and Function of Inflammatory DCs

Notch信号在炎症DC分化和功能中的作用

• 批准号: 8499244
• 负责人: WARREN S PEAR
• 金额: $ 22.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499244
• 关键词: Address; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Blood; Bone Marrow; CSF1R gene; CX3CL1 gene; Cell fusion; Cell physiology; Cells; Chronic; Communicable Diseases; Data; Dendritic Cells; Development; Disease; Disease model; Dominant-Negative Mutation; Equilibrium; Goals; Human; ITGAM gene; ITGAX gene; Immune Tolerance; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Lead; Lymphoid; Molecular; Mus; Myelogenous; Nuclear; Organ; Peritoneum; Phenotype; Play; Population; Regulation; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Site; Spleen; Surface; T cell response; T-Lymphocyte; Testing; Tissues; Transgenic Organisms; base; clinically significant; improved; inhibitor/antagonist; loss of function; lymph nodes; monocyte; notch protein; novel; novel therapeutics; pathogen; programs; secretase; treatment strategy; uptake

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are professional antigen-presenting cells with a central role in adaptive immune responses. They are specialized for the uptake, processing and presentation of antigen to T-cells. By guarding mucosal barriers and transporting antigens to lymphoid organs, they critically control the balance between protective immunity and immune tolerance. Pathogen- induced inflammatory responses lead to the emergence of DCs at the infection site and draining lymph nodes. A significant question is what signals regulate the development and function of DCs at inflammatory foci. Recent research suggests a central role for inflammatory monocytes as major precursors for de novo DC formation during infection. This R21 application presents our plan to understand the role of Notch signaling in the differentiation and function of monocyte-derived DCs (Mo-DC) in chronic inflammation. As outlined in our research approach, we recently identified a unique population of Mo-DCs that have an enhanced ability to undergo cell-cell fusion, a hallmark of chronic inflammation. These cells are absent in steady-state lymphoid organs, however, they are present under inflammatory conditions. We have identified the precursors of these inflammatory DCs in the bone marrow and shown that differentiation in vitro is Notch-dependent. In this proposal, we will address the functional significance of these Notch-dependent Mo-DCs and the role of Notch signaling in the differentiation and function of these cells. We hypothesize that these cells are endowed with the ability to prime effector and/or regulatory T-cell responses and that Notch signaling critically drives both the differentiation and function of these cells. Togethr, these studies should not only lead to an improved understanding of chronic inflammatory disorders but will also identify novel therapeutic strategies for treatment.

描述（由申请人提供）：树突状细胞（DC）是专业的抗原呈递细胞，在适应性免疫反应中具有核心作用。它们专门用于将抗原摄取，加工和表现为T细胞。通过保护粘膜屏障并将抗原运送到淋巴机构，它们可以严格控制保护性免疫和免疫耐受性之间的平衡。病原体诱导的炎症反应导致DC在感染部位出现并排出淋巴结。一个重要的问题是，哪些信号调节DC在炎症焦点下的发展和功能。最近的研究表明，在感染过程中，炎症单核细胞是从头直流形成的主要先驱。该R21应用介绍了我们的计划，以了解Notch信号在慢性炎症中单核细胞衍生的DC（MO-DC）的分化和功能中的作用。正如我们的研究方法中概述的那样，我们最近确定了独特的MO-DC群体，它们具有增强的经历细胞融合的能力，这是慢性炎症的标志。这些细胞在稳态淋巴器官中不存在，但是它们存在于炎症条件下。我们已经确定了骨髓中这些炎性DC的前体，并表明体外分化是依赖性的。在此提案中，我们将解决这些Notch依赖性MO-DC的功能意义，以及Notch信号在这些细胞的分化和功能中的作用。我们假设这些细胞具有主要效应子和/或调节性T细胞响应的能力，并且Notch信号既可以驱动这些细胞的分化和功能。 togethr，这些研究不仅应提高人们对慢性炎症性疾病的了解，而且还将确定新颖的治疗策略。