The role of GPR84 signaling during skin repair

GPR84 信号在皮肤修复中的作用

基本信息

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
项目类别：
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

项目摘要

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.

抽象的有效的伤口愈合需要组织居民之间复杂的细胞通讯非免疫细胞和浸润性免疫细胞的作用已经了解很多。细胞因子和生长因子有助于急性伤口愈合，但我们对其如何作用知之甚少脂质信号传导调节急性炎症和组织修复，并鉴定新的我们之前已经证明了控制急性炎症和修复的机制。抑制真皮脂肪细胞脂肪分解导致早期巨噬细胞数量减少炎症和延迟修复，但将脂肪细胞脂肪分解与有效连接的机制鉴于糖尿病和老年人数量不断增加，炎症和修复尚未确定。对于患者来说，必须定义促进健康急性发作的分子基础炎症反应并确定治疗炎症和非炎症的药物机制愈合伤口。抑制损伤引起的真皮脂肪细胞脂肪分解显着降低丰度最近，GPR84 被确定为 MCFA 受体。由骨髓来源的髓样细胞在组织炎症过程中表达。 GPR84 体外增加巨噬细胞迁移并增强促炎基因然而，其在皮肤中的作用和体内作用机制尚不清楚。观察伤口引起的炎症期间 GPR84 表达增加，发现 GPR84 激动剂的施用会增加巨噬细胞的数量。使用 GPR84 拮抗剂可减少伤口床巨噬细胞和组织延迟根据我们的初步数据，我们敢说需要GPR84信令来支持。损伤引起的炎症期间巨噬细胞的数量和随后的修复。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单细胞数据询问以验证该假设，具体目标如下：(1) 使用小鼠模型以确定 GPR84 信号如何控制巨噬细胞数量损伤后随后的组织修复，以及 (2) 定义 MCFA/GPR84 信号传导如何直接进行在皮肤伤口愈合过程中调节骨髓细胞功能，以及 (3) 定义上皮细胞 GPR84 如何发挥作用信号传导有助于损伤后角质形成细胞的功能。 GPR84 信号传导代表了更好地理解调节机制的新窗口这项拟议工作的结果可以为制定伤害应对措施奠定坚实的基础。预测和增强伤口愈合治疗的新工具。