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:
- 金额:$ 46.57万
- 依托单位:
- 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:
- 关键词:AcuteAdipocytesAgingAgonistBiologyBone MarrowCell CountCell physiologyCellsCellular biologyChronicCommunicationComplexDataDermalDevelopmentDiabetes MellitusDiseaseEpithelial CellsEpitheliumFoundationsG-Protein-Coupled ReceptorsGPR84 geneGene ExpressionGene Expression ProfileGeneticGenetic ModelsGenomicsGoalsGrowth FactorImpaired healingImpaired wound healingIn VitroInflammationInflammatoryInflammatory ResponseInjuryKnockout MiceLearningLinkLipidsLipolysisLoxP-flanked alleleMacrophageMedium chain fatty acidMolecularMusMyelogenousMyeloid CellsPathologicPatientsPhasePopulations at RiskProcessProliferatingQualifyingRegulationRoleSignal PathwaySignal TransductionSkinSkin repairSkin wound healingSolidStromal CellsSystemTestingTherapeuticTherapeutic UsesTissuesWorkacute woundagedantagonistcell typecytokinediabeticexperimental studygenomic toolshealingimmune cell infiltratein vitro Assayin vivoinsightkeratinocytemigrationmouse modelnon-healing woundsnovelpharmacologicpredictive toolsreceptorrecruitrepairedreparative processresponse to injurysingle-cell RNA sequencingsmall moleculestem cellstargeted treatmenttissue repairtoolwoundwound bedwound healingwound 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驻留物之间复杂的细胞通讯
非免疫细胞和浸润性免疫细胞。虽然我们已经了解了很多关于如何
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
需要控制急性炎症和修复的机制。我们之前演示过
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
炎症和修复尚未确定。鉴于糖尿病患者和老年人数量不断增加
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
中链脂肪酸(MCFA)。最近,GPR84被鉴定为MCFA受体
由骨髓来源的髓样细胞和组织炎症期间表达。激活
GPR84 体外增加巨噬细胞迁移并增强促炎基因
表达;然而,其在皮肤中的作用和体内作用机制尚不清楚。我们
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。此外,系统性
使用 GPR84 拮抗剂可减少伤口床巨噬细胞并延迟组织生长
维修。根据我们的初步数据,我们假设需要 GPR84 信号来支持
损伤引起的炎症期间巨噬细胞的数量和随后的修复。我们将
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
伤害反应。这项拟议工作的结果可以为开发奠定坚实的基础
预测和增强伤口愈合治疗的新工具。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
BRETT SHOOK其他文献
BRETT SHOOK的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似国自然基金
支链氨基酸代谢紊乱调控“Adipocytes - Macrophages Crosstalk”诱发2型糖尿病脂肪组织功能和结构障碍的作用及机制
- 批准号:81970721
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
相似海外基金
New development of cellular regeneration therapy in jaw bone using stem cells derived from adipocytes jaw bone
利用颌骨脂肪细胞来源的干细胞进行颌骨细胞再生治疗的新进展
- 批准号:
23K16058 - 财政年份:2023
- 资助金额:
$ 46.57万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
A novel mechanism of insulin resistance mediated by uric acid metabolism in adipocytes
脂肪细胞尿酸代谢介导胰岛素抵抗的新机制
- 批准号:
23K10969 - 财政年份:2023
- 资助金额:
$ 46.57万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Hypertrophic adipocytes as biophysical mediators of breast cancer progression
肥大脂肪细胞作为乳腺癌进展的生物物理介质
- 批准号:
10751284 - 财政年份:2023
- 资助金额:
$ 46.57万 - 项目类别:
Elucidation of mechanisms for conversion of adipocytes to cancer-associated fibroblasts in osteosarcoma microenvironment
阐明骨肉瘤微环境中脂肪细胞转化为癌症相关成纤维细胞的机制
- 批准号:
23K19518 - 财政年份:2023
- 资助金额:
$ 46.57万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Study on UCP-1 independent metabolic regulation by brown adipocytes
棕色脂肪细胞对UCP-1独立代谢调节的研究
- 批准号:
23K18303 - 财政年份:2023
- 资助金额:
$ 46.57万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Development of adipocytes for gene therapy that avoids cellular stress due to overexpression of therapeutic proteins
开发用于基因治疗的脂肪细胞,避免因治疗蛋白过度表达而造成的细胞应激
- 批准号:
23H03065 - 财政年份:2023
- 资助金额:
$ 46.57万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Functional analysis of bitter taste receptors in adipocytes and hepatocytes
脂肪细胞和肝细胞中苦味受体的功能分析
- 批准号:
23K05107 - 财政年份:2023
- 资助金额:
$ 46.57万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
NKA/CD36 signaling in adipocytes promotes oxidative stress and drives chronic inflammation in atherosclerosis
脂肪细胞中的 NKA/CD36 信号传导促进氧化应激并驱动动脉粥样硬化的慢性炎症
- 批准号:
10655793 - 财政年份:2023
- 资助金额:
$ 46.57万 - 项目类别:
The mechanisms of the signal transduction from brown adipocytes to afferent neurons and its significance.
棕色脂肪细胞向传入神经元的信号转导机制及其意义。
- 批准号:
23K05594 - 财政年份:2023
- 资助金额:
$ 46.57万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
NKT cell activation depend on lipid accumulation in adipocytes
NKT 细胞的激活取决于脂肪细胞中的脂质积累
- 批准号:
22K08679 - 财政年份:2022
- 资助金额:
$ 46.57万 - 项目类别:
Grant-in-Aid for Scientific Research (C)














{{item.name}}会员




