Molecular Control of Plasmacytoid Dendritic Cell Development and Function

描述（由申请人提供）：本项目响应通知NOT-OD-09-058，使RPG能够利用NCRR中心和类似中心的计划。浆细胞样树突状细胞（PDC）是一种独特的分泌细胞类型，在先天性免疫反应中起着关键作用。在病毒感染期间，PDC分泌大量的I型干扰素（IFN），引发抗病毒T细胞应答，并激活多种免疫细胞类型。除了感染性免疫外，PDC还参与许多免疫现象，包括抗肿瘤免疫、过敏/哮喘和自身免疫。PDC具有独特的特征和基因表达模式，有利于其直接识别病毒和高水平的IFN分泌。然而，调节PDC谱系定型、成熟和功能的分子机制仍然知之甚少。我们研究的总体目标是在分子水平上剖析PDC发育和功能的调节。我们的工作对父母的补助金已确定E蛋白E2-2作为一个关键的转录调节PDC的发展，在小鼠和人类。我们还发现E2-2直接激活对PDC功能至关重要的转录因子和受体，并鉴定了PDC发育和功能中的新E2-2靶点。与NCRR计划，敲除小鼠项目（KOMP）合作，我们将产生和分析功能丧失的小鼠突变株的几个PDC富集基因的E2-2调节。这些研究将有助于阐明PDC发育和功能的分子基础，从而为针对PDC的免疫学方法铺平道路。 公共卫生部门：该研究旨在对浆细胞样树突状细胞（PDC）进行分子和遗传分析，PDC是一种独特的免疫细胞类型，在抗病毒免疫反应和自身免疫中起着重要作用。 阐明控制PDC发育和功能的分子机制将为靶向感染和自身免疫性疾病中PDC功能的新治疗方法铺平道路。

DESCRIPTION (provided by applicant): This project responds to Notice NOT-OD-09-058, Enabling RPGs to Leverage NCRR Center and Center-like Programs. Plasmacytoid dendritic cells (PDC) represent a unique secretory cell type that plays a critical role in innate immune responses. During viral infections, PDC secrete massive amounts of type I interferon (IFN), prime anti-viral T cell responses, and activate multiple immune cell types. In addition to infectious immunity, PDC are implicated in many immunological phenomena including anti-tumor immunity, allergy/asthma and autoimmunity. The PDC possess unique features and gene expression patterns that facilitate their direct recognition of viruses and high level IFN secretions. However the molecular mechanisms that regulate lineage commitment, maturation, and function of PDC remain poorly understood. The overall goal of our research is to dissect the regulation of PDC development and function at the molecular level. Our work on the parent grant has indentified E protein E2-2 as a key transcriptional regulator of PDC development in mice and humans. We also found the E2-2 directly activated transcriptional factors and receptors critical for pDC function and identified novel E2-2 targets in PDC development and function. In collaboration with the NCRR Program, the Knockout Mouse Project (KOMP), we will generate and analyze loss-of-function mouse mutant strains for several PDC-enriched genes regulate by E2-2. These studies would help elucidate the molecular basis of PDC development and function and thus pave the way for immunotherapeutic approaches directed at the PDC. PUBLIC HEALTH REVELANCE: The study is aimed at molecular and genetic analysis of plasmacytoid dendritic cells (PDC), a unique immune cell type that plays a major role in anti-viral immune responses and in autoimmunity. The elucidation of molecular mechanisms that govern PDC development and function would pave the way for novel therapeutic approaches targeting PDC function in infections and autoimmune diseases.