A novel regulator of dendritic cell differentiation

树突状细胞分化的新型调节剂

基本信息

批准号：
10189518
负责人：
Boris Reizis
金额：
$ 21.19万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-11 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189518
关键词：
Animals Antigens Autoimmunity CRISPR/Cas technology Cell Differentiation process Cell Line Cell physiology Cells Cholesterol Complex Coupling Dendritic Cells Development Disease Dissection FLT3 ligand FRAP1 gene Genes Genetic Genetic Screening Growth Factor Immune system In Vitro Interferon Type I Libraries Ligands Lipids Lysosomes Malignant Neoplasms Mediating Molecular Mus Mutagenesis NPC1 gene Nutrient Pathologic Pathway interactions Pattern recognition receptor Pharmacology Process Production Receptor Protein-Tyrosine Kinases Regulation Role Sentinel Signal Pathway Signal Transduction Signaling Molecule Supraoptic Vertical Ophthalmoplegia Surface T-Lymphocyte TSC1 gene Testing Virus adaptive immune response base cell growth cytokine forward genetics genetic approach genome-wide in vivo insight novel null mutation pathogen prevent progenitor protein complex response therapeutic target

项目摘要

ABSTRACT Dendritic cells (DCs) are key sentinel cells of the immune system that detect pathogens through pattern recognition receptors and orchestrate innate and adaptive immune responses. Conventional DCs (cDCs) efficiently present antigen to T lymphocytes, whereas plasmacytoid DCs (pDCs) specialize in virus-induced production of type I interferon. All DCs and their progenitors express the tyrosine kinase receptor Flt3, and its cytokine ligand Flt3L is necessary and sufficient for DC development. However, relatively little is known about the signaling pathways and molecules that regulate DC differentiation downstream of Flt3L. To dissect the molecular basis of DC differentiation, we implemented an unbiased forward genetics approach utilizing CRISPR/Cas9-based mutagenesis. In addition to known regulators, this approach yielded components of a protein complex that is enriched in DCs but has not been previously implicated in DC differentiation. The proposed project will explore the potential role of this complex in DC differentiation in vitro and in experimental animals (Aim 1) as well as the mechanism of its activity in DCs (Aim 2). If successful, these studies would provide novel insights into the molecular underpinnings of the DC differentiation, including lineage-specific signaling pathways that could be amenable to therapeutic targeting.

抽象的树突状细胞（DCS）是免疫系统的关键前哨细胞，通过模式检测病原体识别受体并协调先天和适应性免疫反应。常规DC（CDC）有效地呈现与T淋巴细胞的抗原，而浆细胞类动物DCS（PDC）专门研究病毒诱导 I型干扰素的生产。所有DC及其祖细胞表达酪氨酸激酶受体FLT3，并且它的细胞因子配体FLT3L是必需的，足以用于直流发育。但是，相对较少已知关于调节FLT3L下游DC分化的信号通路和分子。到解剖DC分化的分子基础，我们实施了一种公正的远期遗传学方法利用基于CRISPR/CAS9的诱变。除了已知的调节剂，这种方法还产生富含DC但以前没有与DC有关的蛋白质复合物的成分分化。拟议的项目将探讨该复合物在DC分化中的潜在作用体外和实验动物（AIM 1）以及其在DC中活性的机制（AIM 2）。如果成功的研究将为DC的分子基础提供新的见解分化，包括可能适合治疗的谱系特异性信号通路定位。