Reprogramming of tissue structural cells by cutaneous CD4+ T cells

皮肤 CD4 T 细胞对组织结构细胞的重编程

• 批准号: 10608777
• 负责人: Daniel J Campbell
• 金额: $ 64.57万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-19 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608777
• 关键词: Address; Atopic Dermatitis; B-Lymphocytes; Behavior; CD4 Positive T Lymphocytes; Cell Culture System; Cell physiology; Cells; Chemicals; Cutaneous; Development; Disease; Drug Targeting; Endothelial Cells; Epigenetic Process; Fibroblasts; Fibrosis; Functional disorder; Genetic Transcription; Host Defense; Human; Immune; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Irritants; Knowledge; Link; Mediator; Memory; Modality; Modification; Monitor; Organism; Pathway interactions; Patients; Pre-Clinical Model; Process; Pruritus; Psoriasis; Resolution; Sampling; Signal Transduction; Site; Skin; Stimulus; System; T cell response; T-Lymphocyte; Therapeutic; Tissue Sample; Tissues; Trauma; Ultraviolet Rays; Vascular Endothelial Cell; cell behavior; cytokine; humanized mouse; in vivo; innovation; keratinocyte; microbial; mouse model; novel; novel therapeutics; pathogen; pre-clinical; prevent; programs; response; skin barrier; skin disorder; targeted treatment; tissue repair; tissue-repair responses

Project Summary/Abstract Although long thought to be a unique feature of adaptive cells such as T and B cells, it is now clear that tissue structural cells can also harbor ‘memory’ of prior inflammatory responses in the form of stable epigenetic modifications that alter their transcriptional potential and behavior following subsequent tissue damage, and this is referred to as ‘inflammatory memory’. This highlights key gaps in our knowledge of T cell-tissue cross- talk that this proposal seeks to address. The premise of this proposal is that cutaneous T cells reprogram local keratinocytes and fibroblasts during inflammation, thereby altering their transcriptional and epigenetic landscape, function, and responses to subsequent stimuli, and that this influences the course and resolution of inflammatory skin disease. To fill these key knowledge gaps, we will examine the cross-talk between T cell and structural cells in innovative cell culture systems to monitor changes in cell behavior and function, and mechanistically link them to transcriptional and epigenetic reprogramming by T cell-derived cytokines. We will also leverage an established and highly manipulatable murine model of T cell-dependent skin inflammation to examine the development of inflammatory memory in KCs and Fibs in vivo, to mechanistically identify important cytokines and epigenetic mediators, and to assess the functional consequences on subsequent inflammatory and tissue-repair responses. Finally, we will analyze signatures of inflammatory memory in tissue samples from patients with the common skin inflammatory diseases psoriasis and atopic dermatitis, and assess epigenetic reprogramming in a preclinical model as a new therapeutic modality to reset inflammatory memory and break the inflammatory cycle in the skin of these patients.

项目概要/摘要 尽管长期以来被认为是 T 细胞和 B 细胞等适应性细胞的独特特征，但现在很清楚，组织 结构细胞还可以以稳定的表观遗传形式储存先前炎症反应的“记忆” 在随后的组织损伤后改变其转录潜力和行为的修饰，以及 这被称为“炎症记忆”，这凸显了我们在 T 细胞组织交叉方面的知识中的关键差距。 该提案旨在解决的问题是皮肤 T 细胞局部重编程。 炎症期间的角质形成细胞和成纤维细胞，改变其转录和表观遗传 景观、功能和对后续刺激的反应，这会影响 为了填补这些关键知识空白，我们将研究 T 细胞和炎症性皮肤病之间的相互作用。 创新细胞培养系统中的结构细胞，用于监测细胞行为和功能的变化，以及 我们将在机制上将它们与 T 细胞衍生的细胞因子的转录和表观遗传重编程联系起来。 还利用已建立的、高度可操作的 T 细胞依赖性皮肤炎症小鼠模型 检查体内 KC 和 Fib 中炎症记忆的发展，以机械方式识别 重要的细胞因子和表观遗传介质，并​​评估对后续的功能后果 最后，我们将分析组织中炎症记忆的特征。 来自患有常见皮肤炎症疾病牛皮癣和特应性皮炎的患者的样本，以及 在临床前模型中评估表观遗传重编程作为重置炎症的新治疗方式 记忆并打破这些患者皮肤的炎症循环。