Molecular Control of Plasmacytoid Dendritic Cell Development and Function

描述（由申请人提供）：该项目响应no - od -09-058号通知，使rpg能够利用NCRR中心和类似中心的项目。浆细胞样树突状细胞（PDC）是一种独特的分泌细胞类型，在先天免疫应答中起关键作用。在病毒感染期间，PDC分泌大量I型干扰素（IFN），引发抗病毒T细胞反应，并激活多种免疫细胞类型。除感染免疫外，PDC还涉及许多免疫现象，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，有助于它们直接识别病毒和高水平IFN分泌物。然而，调控PDC的谱系承诺、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发育和功能的调控。我们在亲本研究中发现E蛋白E2-2是小鼠和人类PDC发育的关键转录调节因子。我们还发现E2-2直接激活pDC功能的转录因子和受体，并确定了新的E2-2在pDC发育和功能中的靶点。我们将与NCRR项目、敲除小鼠项目（KOMP）合作，生成并分析E2-2调控的几种富含pdc的基因的功能缺失小鼠突变株。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.