The role of GPR84 signaling during skin repair

GPR84 信号在皮肤修复中的作用

• 批准号: 10637039
• 负责人: BRETT SHOOK
• 金额: $ 46.57万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637039
• 关键词: Acute; Adipocytes; Aging; Agonist; Biology; Bone Marrow; Cell Count; Cell physiology; Cells; Cellular biology; Chronic; Communication; Complex; Data; Dermal; Development; Diabetes Mellitus; Disease; Epithelial Cells; Epithelium; Foundations; G-Protein-Coupled Receptors; GPR84 gene; Gene Expression; Gene Expression Profile; Genetic; Genetic Models; Genomics; Goals; Growth Factor; Impaired healing; Impaired wound healing; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Learning; Link; Lipids; Lipolysis; LoxP-flanked allele; Macrophage; Medium chain fatty acid; Molecular; Mus; Myelogenous; Myeloid Cells; Pathologic; Patients; Phase; Populations at Risk; Process; Proliferating; Qualifying; Regulation; Role; Signal Pathway; Signal Transduction; Skin; Skin repair; Skin wound healing; Solid; Stromal Cells; System; Testing; Therapeutic; Therapeutic Uses; Tissues; Work; acute wound; aged; antagonist; cell type; cytokine; diabetic; experimental study; genomic tools; healing; immune cell infiltrate; in vitro Assay; in vivo; insight; keratinocyte; migration; mouse model; non-healing wounds; novel; pharmacologic; predictive tools; receptor; recruit; repaired; reparative process; response to injury; single-cell RNA sequencing; small molecule; stem cells; targeted treatment; tissue repair; tool; wound; wound bed; wound healing; wound treatment

ABSTRACT Efficient wound healing requires complex cellular communication between tissue-resident non-immune cells and infiltrating immune cells. While much has been learned about how cytokines and growth factors contribute to acute wound healing, we know very little about how lipid signaling regulates acute inflammation and tissue repair, and identification of new mechanisms that govern acute inflammation and repair is needed. We previously demonstrated that inhibiting dermal adipocyte lipolysis led to reduced macrophage numbers during early inflammation and delayed repair, yet the mechanism(s) linking adipocyte lipolysis to efficient inflammation and repair have not been identified. Given the rising numbers of diabetic and aged patients, it is imperative to define molecular underpinnings that promote a healthy acute inflammatory response and to identify druggable mechanisms to treat inflammation and non- healing wounds. Inhibition of injury-induced dermal adipocyte lipolysis significantly reduces the abundance of medium-chain fatty acids (MCFAs). Recently, GPR84 was identified to be an MCFA receptor that is expressed by bone marrow-derived myeloid cells and during tissue inflammation. Activation of GPR84 in vitro increases macrophage migration and enhances pro-inflammatory gene expression; however, its role in skin and the in vivo mechanism of action is not well defined. We observe increased GPR84-expression during wound-induced inflammation and found that administration of a GPR84 agonist increases macrophage numbers. Additionally, systemic administration of a GPR84 antagonist decreases wound bed macrophages and delays tissue repair. Based on our preliminary data, we hypothesize that GPR84 signaling is required to support macrophage numbers and subsequent repair during injury-induced inflammation. We will combine our team’s tools and expertise in adipocyte, keratinocyte, and macrophage biology with single-cell data interrogation to validate this hypothesis with the following Specific Aims: (1) Use mouse models to determine how GPR84 signaling controls macrophage numbers and subsequent tissue repair after injury, and (2) define how MCFA/GPR84 signaling directly regulates myeloid cell function during skin wound healing and (3) define how epithelial GPR84 signaling contributes to keratinocyte function after injury. GPR84 signaling represents a new window to better understand mechanisms that regulate the injury response. Findings from this proposed work could lay a solid foundation for developing new tools that predict and enhance therapeutic treatment of wound healing.

摘要 有效的伤口愈合需要组织驻留之间复杂的细胞通讯 非免疫细胞和浸润性免疫细胞。虽然已经了解了很多关于如何 细胞因子和生长因子在急性伤口愈合中起作用，我们对此知之甚少。 脂质信号调节急性炎症和组织修复，并识别新的 管理急性炎症和修复的机制是必要的。我们之前演示过 抑制真皮脂肪细胞脂解导致早期巨噬细胞数量减少 炎症和延迟修复，然而将脂肪细胞脂肪分解与有效联系起来的机制(S) 炎症和修复尚未确定。鉴于糖尿病和老年人的数量不断增加 患者，必须定义促进健康急性呼吸道疾病的分子基础 炎症反应并确定治疗炎症和非炎症的可用药机制 愈合伤口。 抑制损伤诱导的真皮脂肪细胞脂肪分解显著降低其丰度 中链脂肪酸(MCFA)。最近，GPR84被鉴定为MCFA受体 它在骨髓来源的髓系细胞和组织炎症中表达。激活 GPR84体外促进巨噬细胞迁移并增强促炎基因 然而，它在皮肤中的作用和在体内的作用机制还没有很好地确定。我们 观察创伤诱导的炎症过程中GPR84表达的增加，发现 给予GPR84激动剂可增加巨噬细胞数量。此外，系统性 应用GPR84拮抗剂减少伤口巨噬细胞并延迟组织 修理。根据我们的初步数据，我们假设GPR84信令需要支持 损伤诱导炎症过程中巨噬细胞的数量和随后的修复。我们会 将我们团队在脂肪细胞、角质形成细胞和巨噬细胞生物学方面的工具和专业知识与 用单细胞数据询问来验证这一假设的具体目的如下：(1)使用 小鼠模型以确定GPR84信号如何控制巨噬细胞数量和 以及(2)确定MCFA/GPR84如何直接传递信号 调节皮肤创伤愈合过程中的髓系细胞功能和(3)定义上皮GPR84如何 信号转导有助于角质形成细胞在损伤后的功能。 GPR84信号代表了一个新的窗口，可以更好地理解调控机制 伤害反应。这项拟议工作的发现可以为开发 预测和加强伤口愈合治疗的新工具。