Molecular Control of Plasmacytoid Dendritic Cell Development and Function

浆细胞样树突状细胞发育和功能的分子控制

• 批准号: 10583989
• 负责人: Boris Reizis
• 金额: $ 61.79万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583989
• 关键词: Address; Antiviral Response; Autoimmune Diseases; Autoimmunity; Award; Cell Lineage; Cellular biology; Dendritic Cells; Development; E protein; Goals; Heterogeneity; Homeostasis; Immune response; Infection; Instruction; Interferon Type I; Interferon alpha; Interferons; Methods; Molecular; Nucleic Acids; Play; Production; Regulation; Role; Specific qualifier value; TCF7L2 gene; Therapeutic; Transcriptional Regulation; Virus; Work; cell type; genetic approach; high dimensionality; human disease; in vivo; novel; response; single cell analysis; therapeutic target; translational approach; Address; Antiviral Response; Autoimmune Diseases; Autoimmunity; Award; Cell Lineage; Cellular biology; Dendritic Cells; Development; E protein; Goals; Heterogeneity; Homeostasis; Immune response; Infection; Instruction; Interferon Type I; Interferon alpha; Interferons; Methods; Molecular; Nucleic Acids; Play; Production; Regulation; Role; Specific qualifier value; TCF7L2 gene; Therapeutic; Transcriptional Regulation; Virus; Work; cell type; genetic approach; high dimensionality; human disease; in vivo; novel; response; single cell analysis; therapeutic target; translational approach

Plasmacytoid dendritic cells (pDCs) rapidly secrete type I interferon (interferon α/β, IFN) in response to virus- derived nucleic acids, facilitating both innate and adaptive antiviral responses. Conversely, aberrant IFN production by pDCs is associated with autoimmune diseases, establishing pDCs as important emerging therapeutic targets. The overall goal of this project is to elucidate the molecular control of pDCs lineage, including its development, homeostasis and function in various immune responses. In the previous award cycles, we have identified E protein transcription factor TCF4 (E2-2) and several other factors as important regulators of pDC development. The proposed work will build upon these findings to address major unanswered questions in pDC biology. In Aim 1, we will use high-dimensional single-cell analysis methods to characterize the stage and regulation of pDC lineage specification, as well as the functional heterogeneity of mature pDCs. In Aim 2, we will use genetic approaches to dissect transcriptional control and regulation of the unique IFN-producing capacity of pDCs. In Aim 3, we will explore the mechanism of virus recognition and IFN production by pDCs in vivo. Collectively, the proposed studies should yield a comprehensive molecular view of pDC development and function, paving the way for therapeutic approaches focused on this cell type. RELEVANCE (See instructions): Plasmacytoid dendritic cells (pDCs) play an important role in immune responses to infection and in autoimmunity, and therefore represent attractive targets for novel immunoterapies. The proposed work aims to build a comprehensive molecular view of pDC development and function, paving the way for pDCfocused translational approaches in human diseases.

浆细胞样树突状细胞（PDC）迅速分泌I型干扰素（干扰素α/β，IFN）对病毒的反应 衍生的核酸，支持先天和适应性抗病毒反应。相反，异常IFN PDC的生产与自身免疫性疾病有关，将PDC确定为重要的新兴 治疗靶标。该项目的总体目标是阐明PDC谱系的分子控制， 包括其发育，体内稳态和各种免疫反应中的功能。在上一个奖项中 周期，我们已经确定了E蛋白转录因子TCF4（E2-2）和其他几个因素很重要 PDC开发的监管机构。拟议的工作将基于这些发现以解决专业 PDC生物学中未解决的问题。在AIM 1中，我们将使用高维单细胞分析方法 表征PDC谱系规范的阶段和调节以及功能异质性 成熟的PDC。在AIM 2中，我们将使用遗传方法来剖析转录控制和调节 PDC的独特产能。在AIM 3中，我们将探讨病毒识别的机制和 PDC在体内产生IFN。总体而言，拟议的研究应产生全面的分子 PDC开发和功能的视图，为这种细胞类型的治疗方法铺平了道路。 相关性（请参阅说明）： 浆细胞类动物树突状细胞（PDC）在免疫回报中起着重要作用 自身免疫性，因此代表了新型免疫环境的有吸引力的靶标。拟议的工作目的 为了建立PDC开发和功能的综合分子视图，为PDCFOCUSE铺平了道路 人类疾病的翻译方法。