Elucidating the Cellular and Molecular Mechanisms of How Regulatory T cells in Skin Regulate Fibroblast Activation and Tissue Fibrosis

阐明皮肤中调节性 T 细胞如何调节成纤维细胞活化和组织纤维化的细胞和分子机制

• 批准号: 10398162
• 负责人: Michael David Rosenblum
• 金额: $ 34.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398162
• 关键词: Adult; Affinity; Applications Grants; Attenuated; Binding; Biological; Biology; Birth; Bleomycin; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chimeric Proteins; Chronic; Cutaneous; Data; Deposition; Dermal; Disease; Engineering; Extracellular Matrix; Fibroblasts; Fibrosis; GATA3 gene; Genetic Transcription; Goals; Heterogeneity; Homeostasis; Human; Immune; Immune response; Immunity; Immunoglobulin G; In Vitro; Inflammation; Interleukin 2 Receptor; Interleukin-10; Interleukin-13; Interleukin-2; Interleukin-4; Interleukin-5; Knowledge; Life; Link; Mediating; Modeling; Molecular; Mus; Pathogenesis; Pathologic; Pathway interactions; Pharmacology; Physiological Processes; Play; Population; Population Replacements; Process; Production; Property; Proteins; Regulation; Regulatory T-Lymphocyte; Role; Scleroderma; Signal Transduction; Skin; Testing; Time; Tissues; Wound models; cell type; cytokine; effector T cell; experimental study; human model; humanized mouse; in vivo; in vivo Model; innovation; insight; lymphoid organ; macrophage; mouse model; mutein 2; novel; novel therapeutic intervention; novel therapeutics; programs; skin fibrosis; skin organogenesis; tissue repair; transcriptome; wound; wound healing

Project Summary/Abstract Regulatory T cells (Tregs) play a major role in establishing and maintaining immune homeostasis. However, an emerging body of work suggests that these cells have `specialized' functions in tissues in addition to their role as immune regulatory cells. We have discovered that Tregs in skin play a critical role in regulating fibroblast activation and dermal fibrosis in both mouse and humanized mouse models. In addition, we have generated a novel protein that selectively activates Tregs in vivo. The underlying theme of this proposal is to functionally dissect the dominant cellular and molecular mechanisms utilized by Tregs in skin to influence fibroblast function. We will also discern whether in vivo activation of Tregs results in a diminution of skin fibrosis. The experiments outlined herein represent a conceptually and technically innovative, systematic approach to better understand how Tregs influence the biology of skin fibroblasts. In doing so, we will undercover a critical mechanistic link between two skin-resident cell populations with clear and evident impact on tissue function. Our results may have direct implications for wound healing and/or chronic fibrosing diseases, with the possibility of uncovering a new therapeutic strategy for these conditions.

项目总结/摘要 调节性T细胞（Regulatory T cells，Tcells）在建立和维持免疫稳态中起主要作用。然而，一个新兴的 大量的研究表明，这些细胞除了作为免疫调节细胞外，在组织中还具有“专门的”功能 细胞我们已经发现，皮肤中的TdR在调节成纤维细胞活化和真皮纤维化中起关键作用， 小鼠和人源化小鼠模型。此外，我们已经产生了一种新的蛋白质，它选择性地激活TcR。 in vivo.这项建议的基本主题是从功能上剖析占主导地位的细胞和分子 皮肤中TdR利用的影响成纤维细胞功能的机制。我们还将辨别体内激活 结果皮肤纤维化减少。本文概述的实验在概念上和技术上代表了一种新的方法。 创新的，系统的方法，以更好地了解THBE如何影响皮肤成纤维细胞的生物学。这样做 将揭示两种皮肤驻留细胞群之间的关键机制联系，对 组织功能我们的研究结果可能对伤口愈合和/或慢性纤维化疾病有直接影响， 为这些疾病发现新的治疗策略的可能性。

项目成果

Regulatory T cells promote innate inflammation after skin barrier breach via TGF-β activation.

• DOI: 10.1126/sciimmunol.abg2329
• 发表时间: 2021-08-27
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Moreau JM;Dhariwala MO;Gouirand V;Boda DP;Boothby IC;Lowe MM;Cohen JN;Macon CE;Leech JM;Kalekar LA;Scharschmidt TC;Rosenblum MD
• 通讯作者: Rosenblum MD