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

• 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
• 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

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.

抽象的 朗格汉斯细胞 (LC) 是皮肤中的树突状细胞 (DC)，控制适应性免疫 和皮肤的免疫耐受性，并参与多种皮肤病的发展。 转化生长因子-β1 (TGFβ1) 是 LC 维持和功能的关键因素。 TGFβ1 通过与 TGFb 受体相互作用发出信号来激活 Smad 依赖性或 Smad 独立途径调节 TGFb1 靶基因和细胞功能。 信号通路、TGFb1 介导的 LC 维持的详细分子网络以及 TGFb1在胚胎LC中的功能调控、具体作用及相关机制 我们最近的工作和初步研究表明 TGFb1 的发展仍不清楚。 胚胎 LC 发育绝对必需，其中 TGFβ 激活激酶 1 (Tak1) 和 主导 TGFb1 信号通路的是 Tak1，而不是 Smads； LC 产后分化；并且 Smad 信号通路在炎症过程中占主导地位 这些结果强烈表明不同的 TGFb 信号通路。 介导胚胎个体发育与产后稳态或炎症中的 LC 调节 在拟议的研究中，将使用不同的空间和时间特异性和 结合RNA-seq、scRNA-seq、ChIP-Seq的瞬时诱导基因突变小鼠模型， 成像FACS，以及体内/体外慢病毒介导的基因激活和删除策略， 旨在破译 TGFb 信号通路的上下文相关特异性及相关 调节 LC 个体发育、产后稳态和再增殖结果的分子网络。 拟议的研究不仅将加深我们对 LC 生物学的理解，而且还将揭示 对治疗 LC 相关疾病具有高特异性的潜在治疗靶点的新认识 疾病。

项目成果

microRNA dynamic expression regulates invariant NKT cells.

microRNA 动态表达调节不变的 NKT 细胞。

• 发表时间: 2021-08
• 作者: Mi, Qing;Wang, Jie;Liu, Queping;Wu, Xiaojun;Zhou, Li
• 通讯作者: Zhou, Li

MiR-23a Regulates Skin Langerhans Cell Phagocytosis and Inflammation-Induced Langerhans Cell Repopulation.

MiR-23a 调节皮肤朗格汉斯细胞吞噬作用和炎症诱导的朗格汉斯细胞再生。

• 发表时间: 2023-06-28
• 影响因子: 4.2
• 作者: Wang, Jie;Parajuli, Nirmal;Wang, Qiyan;Khalasawi, Namir;Peng, Hongmei;Zhang, Jun;Yin, Congcong;Mi, Qing;Zhou, Li
• 通讯作者: Zhou, Li