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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.

摘要