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.

抽象的 有效的逻辑愈合需要组织居民之间复杂的细胞通信 非免疫细胞和浸润的免疫细胞。虽然已经了解了如何 细胞因子和生长因素导致急性伤口愈合，我们对如何了解 脂质信号传导调节急性炎症和组织修复，并确定新的 需要控制急性炎症和修复的机制。我们以前证明了 抑制真皮脂肪细胞脂解会导致早期巨噬细胞数量减少 炎症和延迟修复，但是将脂肪细胞脂解与有效的机制 尚未确定炎症和修复。鉴于糖尿病和老年数量增加 患者，必须定义促进健康急性的分子基础 炎症反应并确定可药物的机制来治疗炎症和非 - 治愈逻辑。 抑制损伤诱导的皮肤脂肪细胞脂解会显着降低丰度 中链脂肪酸（MCFAS）。最近，GPR84被确定为MCFA接收器 这是由骨髓衍生的髓样细胞和在组织注射过程中表达的。激活 GPR84体外增加巨噬细胞迁移并增强促炎基因 表达;但是，其在皮肤中的作用和体内作用机理的作用尚未得到很好的定义。我们 观察到伤口引起的注射期间GPR84表达增加，发现 GPR84激动剂的给药增加了巨噬细胞数量。另外，系统性 GPR84拮抗剂的给药会降低伤口床巨噬细胞并延迟组织 维修。根据我们的初步数据，我们假设需要GPR84信号来支持 巨噬细胞数量和随后的损伤诱导注射。我们将 将我们的团队在脂肪细胞，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 单细胞数据询问以验证以下特定目的验证该假设：（1）使用 鼠标模型确定GPR84信号如何控制巨噬细胞数量和 受伤后随后的组织修复，（2）定义MCFA/GPR84如何直接信号传导 调节皮肤伤口愈合过程中的髓样细胞功能，（3）定义上皮GPR84 信号传导损伤后有助于角质形成细胞功能。 GPR84信号代表了一个新窗口，以更好地了解调节的机制 伤害反应。这项拟议工作的发现可以为发展奠定坚实的基础 预测和增强伤口愈合治疗的新工具。