Novel transcription factors modulating the development and function of pDCs and pDC-related cells

调节 pDC 和 pDC 相关细胞发育和功能的新型转录因子

基本信息

批准号：
10288643
负责人：
Juliana Idoyaga
金额：
$ 23.81万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288643
关键词：
Antiviral Agents Binding Biological Assay Cell Lineage Cell Maintenance Cell Proliferation Cell physiology Cells Charge Chromatin Collaborations Data Dendritic Cells Development Disease Fibrinogen Gene Expression Genetic Genetic Transcription Genomics Goals Human Human Cell Line ID2 gene Immune Immune response Individual Innate Immune Response Interferon Type I Interferons Knockout Mice Light Maintenance Modeling Mus Natural Killer Cells Outcome Play Regulation Research Role Site T-Cell Activation T-Lymphocyte TCF7L2 gene Testing Therapeutic Tissues Transcriptional Regulation Transposase Viral Virus Virus Diseases base cell type conditional knockout design genome-wide high dimensionality immunoregulation innate immune function mouse model new therapeutic target novel overexpression pathogen programs recruit response therapeutic development transcription factor

项目摘要

ABSTRACT Plasmacytoid dendritic cells (pDCs) and pDC-related cells are developmentally related innate immune cells capable of performing multiple functions essential for successful antiviral immune responses, including type I interferon secretion and T cell activation. The identity, i.e., development and function, of pDCs and pDC-related cells is controlled by the precise interaction of transcription factors (TFs). Tight regulation of transcriptional programs is essential to promote the appropriate response to pathogens while avoiding damage to healthy tissues. Thus, it is critical to unravel the transcriptional regulation of pDCs and pDC-related cells. Using a high- dimensional unbiased approach, we have recently discovered two conserved TFs that are specific and highly active in pDCs and pDC-related cells but not in other DC subsets. In two specific aims, we propose to explore the role of these TFs in determining the development and function of pDCs and pDC-related cells. To achieve our goal, we will take advantage of novel conditional knockout mouse models, transcription factor- overexpressing human cell lines, and high-dimensional approaches already established in our lab. We anticipate that findings from this proposal will bring into light novel mechanisms of transcriptional regulation that result in the positive outcome of innate immune responses against viruses. Importantly, our integrated approach will incorporate analyses of both mouse and human DCs; thus, it can reveal features that are conserved between species. This proposal has the potential to impact the rational design of therapeutic strategies by exploring regulatory programs determining the identity of key antiviral innate cells.

抽象的浆细胞样树突状细胞 (pDC) 和 pDC 相关细胞是发育相关的先天免疫细胞能够执行成功抗病毒免疫反应所必需的多种功能，包括 I 型免疫反应干扰素分泌和 T 细胞激活。 pDC 和 pDC 相关的身份，即发育和功能细胞由转录因子 (TF) 的精确相互作用控制。转录的严格调控计划对于促进对病原体的适当反应，同时避免对健康造成损害至关重要组织。因此，阐明 pDC 和 pDC 相关细胞的转录调控至关重要。使用高通过维度无偏的方法，我们最近发现了两个保守的转录因子，它们是特异性的且高度在 pDC 和 pDC 相关细胞中活跃，但在其他 DC 亚群中不活跃。为了实现两个具体目标，我们建议探索这些转录因子在决定 pDC 和 pDC 相关细胞的发育和功能中的作用。达到我们的目标，我们将利用新型条件敲除小鼠模型，转录因子- 过度表达人类细胞系，以及我们实验室已经建立的高维方法。我们预计该提案的发现将揭示转录调控的新机制，从而导致针对病毒的先天免疫反应的积极结果。重要的是，我们的综合方法将结合小鼠和人类 DC 的分析；因此，它可以揭示之间保守的特征物种。该提案有可能通过探索来影响治疗策略的合理设计确定关键抗病毒先天细胞身份的监管程序。