A novel regulator of dendritic cell differentiation

树突状细胞分化的新型调节剂

• 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
• 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

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.

摘要