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Decoding TGF-beta signaling pathways in skin langerhans cells

解码皮肤朗格汉斯细胞中的 TGF-β 信号通路

基本信息

批准号：
10541915
负责人：
QING-SHENG MI
金额：
$ 37.63万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541915
关键词：
Adult Affect Amino Acids Antigen-Presenting Cells BCL2 gene Binding Biology Birth Bone Marrow Cell Maintenance Cell Nucleus Cell Ontogeny Cell physiology Cellular biology ChIP-seq Cytoplasm Data Defect Dendritic Cells Development Disease Embryo Embryonic Development Epidermis FRAP1 gene Family Fetal Liver Gene Activation Gene Deletion Gene Mutation Genes Genetic Goals Growth Homeostasis ITGAM gene Image Immune Tolerance Impairment In Vitro Individual Inflammation Inflammatory Interruption Langerhans cell Lead Lentivirus Light MAPK8 gene Macrophage Colony-Stimulating Factor Receptor Maintenance Mediating Membrane Mitogen-Activated Protein Kinases Molecular Mus Myelogenous Pathway interactions Peripheral Phosphorylation Phosphotransferases Population Procedures Proteins RUNX3 gene Regulation Reporting Research Role Signal Pathway Signal Transduction Skin Specificity TF gene TGF Beta Signaling Pathway TRAF6 gene Testing Transforming Growth Factor beta Transforming Growth Factors Work Yolk Sac activating transcription factor 3 adaptive immunity blastomere structure density experience gene function gene network in vivo macrophage monocyte mouse model p38 Mitogen Activated Protein Kinase postnatal pregnant promoter receptor recruit self-renewal single-cell RNA sequencing skin disorder therapeutic target transcriptome sequencing

项目摘要

Abstract Langerhans cells (LCs), the skin residing dendritic cells (DCs), control both adaptive immunity and immune tolerance in skin and are involved in the development of a variety of skin diseases. Transforming growth factor-β1 (TGFβ1) is a crucial factor for LC maintenance and function. TGFβ1 signals through interactions with TGFb receptors to activate either Smad-dependent or Smad-independent pathways to regulate TGFb1 target genes and cellular function. However, the signaling pathways, the detailed molecular networks of TGFb1-mediated LC maintenance and functional regulation, and the specific role of TGFb1 and related mechanisms in embryonic LC development remain unclear. Our recent work and preliminary studies showed that TGFb1 is absolutely required for embryonic LC development, in which TGFβ-activated kinase 1 (Tak1), and not Smads, leads the dominant TGFb1 signaling pathway; that Tak1, not Smads, is involved in LC postnatal differentiation; and that Smad signaling pathways are dominant during inflammation- induced LC repopulation. These results strongly suggest that diverse TGFb signaling pathways mediate LC regulations in embryonic ontogeny versus postnatal homeostasis or inflammation- induced repopulation. In the proposed studies, will use different spatial- and temporal-specific and transient inducible gene mutation mouse models combined with RNA-seq, scRNA-seq, ChIP-Seq, imaging FACS, and in vivo/in vitro lentivirus-mediated gene activation and deletion strategies, aiming to decipher the context-dependent specificities of TGFb signaling pathways and related molecular networks that regulate LC ontogeny, postnatal homeostasis, and repopulation. Results from the proposed studies will not only further our understanding of LC biology, but also will shed new light on potential therapeutic targets with high specificity for the treatment of LC-related diseases.

摘要朗格汉斯细胞（LC），皮肤驻留树突状细胞（DC），控制适应性免疫和免疫功能。和皮肤中的免疫耐受性，并参与多种皮肤疾病的发展。转化生长因子-β1（transforminggrowthfactor-β 1，TGFβ1）是LC维持和功能的关键因子。 TGFβ1通过与TGF β受体相互作用来激活Smad依赖性或 Smad非依赖性途径调节TGF β 1靶基因和细胞功能。但信号通路，TGF β 1介导的LC维持的详细分子网络， TGF β 1在胚胎LC中的作用及其相关机制发展仍不明朗。我们最近的工作和初步研究表明，TGF β 1是胚胎LC发育所必需的，其中TGFβ激活的激酶1（Tak 1），和主导TGFb 1信号通路的是Tak 1，而不是Smads; LC出生后分化; Smad信号通路在炎症过程中占主导地位- 诱导LC再增殖。这些结果有力地表明，不同的TGF β信号通路，介导LC调节胚胎个体发育与出生后的稳态或炎症- 诱导繁殖。在拟议的研究中，将使用不同的空间和时间特定的，瞬时诱导基因突变小鼠模型与RNA-seq、scRNA-seq、ChIP-Seq、成像流式细胞仪，以及体内/体外慢病毒介导的基因激活和缺失策略，目的是破译TGF β信号通路和相关的环境依赖性特异性，调节LC个体发育、出生后体内平衡和再增殖的分子网络。结果从拟议的研究不仅将进一步我们了解LC生物学，而且将摆脱对治疗LC相关的高特异性潜在治疗靶点的新认识疾病