Macrophage Phenotypes and Tissue Repair
巨噬细胞表型和组织修复
基本信息
- 批准号:10153826
- 负责人:
- 金额:$ 49.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptedAntidiabetic DrugsBiological ProcessCellsChronicClinical ResearchClinical TrialsDataDevelopmentDiabetes MellitusDiabetic mouseFormulationFutureGlyburideGoalsHumanImpaired healingImpaired wound healingImpairmentInflammasomeInflammationInflammatoryInflammatory ResponseInjuryInvestigational DrugsLaboratoriesLeg UlcerMethodsModelingMusMuscleMuscle FibersNatural regenerationOrganismPathway interactionsPhasePhenotypePlayPopulationProcessPublishingRegulationResearchResolutionRoleShapesSkeletal MuscleSkinSkin repairSkin wound healingTechniquesTissuesTopical applicationTranslatingVisiondiabeticexperimental studyhealingimprovedin vivoinsightmacrophagemonocytenovelnovel strategiesnovel therapeuticspathogenrepairedsingle cell analysistissue repairtranscription factorwoundwound healing
项目摘要
PROJECT SUMMARY
The long term goals of my laboratory are to generate new insights into the role of the
inflammatory response in tissue repair and to develop novel therapies that shape the
inflammatory response to improve tissue repair. For the past 15 years, the major focus of my
research has been the role of macrophages in tissue damage, repair and regeneration. My
laboratory has published findings that macrophages play important roles in repair of both skin
and skeletal muscle and that these cells display tremendous phenotypic plasticity while helping
to guide a wound through each phase of healing. Our data also demonstrate that macrophage
dysregulation contributes to chronic inflammation and impaired skin wound healing in diabetes
as well as impaired healing of traumatic muscle injuries. Importantly, we have demonstrated and
that targeting macrophages can induce resolution of inflammation and improve healing. For
example, we have found that repurposing the anti-diabetic drug glyburide into a topical
treatment for skin wound healing can be used to inhibit the NLRP3 inflammasome in wounds,
which results in a switch from a destructive pro-inflammatory to a pro-healing macrophage
phenotype and improved healing in diabetic mice. We are now in the process of obtaining an
Investigational New Drug designation for our new formulation that is needed to move forward
into a Phase I human trial on topical glyburide for diabetic leg ulcers. Following this model
pipeline from discovery to clinical trial will be a primary goal of all our future studies.
Despite these advances, much remains to be learned about the plasticity of macrophages
during tissue repair and the factors that regulate macrophage function, including cell-intrinsic
and cell-extrinsic pathways. To this end, my laboratory is studying the contributions of each
developmental stage of the monocyte/macrophage lineage to the regulation of wound
macrophage function during repair of skin and skeletal muscle, in both normal healing and
impaired healing models, in mice and humans. A goal of my laboratory over the next 5 years is
to take advantage of newly developed single cell analysis techniques to determine, using
unbiased methods, the actual phenotypes that macrophages adopt during normal and impaired
wound healing. This approach will help overcome a significant barrier to progress in the field,
which is the widespread use of biased and oversimplistic methods to categorize macrophage
populations in vivo, and has potential to identify novel macrophage populations involved in
healing. We will also use the single cell analysis techniques to guide mechanistic experiments
to elucidate the transcription factors and pathways involved in the regulation of different
macrophage populations. As our research progresses, we plan to address additional significant
gaps in understanding in the wound healing field, including the role of wound pathogens in the
(dys)regulation of macrophage function and tissue repair. The overall vision guiding our
approach is that by identifying novel regulators of macrophage function during wound healing,
we can develop new approaches to manipulate inflammation and improve healing of poorly
healing wounds, and in the process, generate a pipeline of candidate therapies to translate into
clinical studies.
项目概要
我实验室的长期目标是对科学的作用产生新的见解
组织修复中的炎症反应并开发新的疗法来塑造
炎症反应以改善组织修复。在过去的 15 年里,我的主要关注点是
研究人员一直在研究巨噬细胞在组织损伤、修复和再生中的作用。我的
实验室发表的研究结果表明巨噬细胞在皮肤修复中发挥重要作用
和骨骼肌,这些细胞表现出巨大的表型可塑性,同时帮助
引导伤口经历愈合的每个阶段。我们的数据还表明巨噬细胞
调节失调会导致糖尿病患者的慢性炎症和皮肤伤口愈合受损
以及创伤性肌肉损伤的愈合受损。重要的是,我们已经证明并
靶向巨噬细胞可以诱导炎症消退并改善愈合。为了
例如,我们发现将抗糖尿病药物格列本脲重新调整为外用药物
皮肤伤口愈合的治疗可用于抑制伤口中的NLRP3炎性体,
这导致从破坏性促炎细胞转变为促愈合巨噬细胞
糖尿病小鼠的表型和改善的愈合。我们现在正在获得一个
我们新配方的研究性新药指定需要继续推进
进入局部格列本脲治疗糖尿病腿部溃疡的 I 期人体试验。遵循这个模型
从发现到临床试验的管道将是我们未来所有研究的主要目标。
尽管取得了这些进展,但关于巨噬细胞的可塑性仍有很多东西需要了解
在组织修复过程中以及调节巨噬细胞功能的因素,包括细胞内在的
和细胞外源性途径。为此,我的实验室正在研究每个人的贡献
单核细胞/巨噬细胞谱系的发育阶段对伤口的调节
巨噬细胞在皮肤和骨骼肌修复过程中的功能,无论是正常愈合还是
小鼠和人类的愈合模型受损。我实验室未来5年的目标是
利用新开发的单细胞分析技术来确定、使用
无偏见的方法,巨噬细胞在正常和受损期间采用的实际表型
伤口愈合。这种方法将有助于克服该领域取得进展的重大障碍,
这是广泛使用有偏见和过于简单化的方法来对巨噬细胞进行分类
体内群体,并有潜力识别参与的新巨噬细胞群体
康复。我们还将使用单细胞分析技术来指导机械实验
阐明参与不同调节的转录因子和途径
巨噬细胞群。随着研究的进展,我们计划解决更多重要问题
对伤口愈合领域的理解存在差距,包括伤口病原体在伤口愈合中的作用
巨噬细胞功能和组织修复的(失调)调节。指导我们的总体愿景
方法是通过识别伤口愈合过程中巨噬细胞功能的新调节因子,
我们可以开发新方法来控制炎症并改善不良症状的愈合
治愈伤口,并在此过程中产生一系列候选疗法,并将其转化为
临床研究。
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 }}
TIMOTHY J KOH其他文献
TIMOTHY J KOH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 }}
{{ truncateString('TIMOTHY J KOH', 18)}}的其他基金
The Role of Macrophages in Vesicant Skin Injury and Repair
巨噬细胞在水疱性皮肤损伤和修复中的作用
- 批准号:
10667174 - 财政年份:2023
- 资助金额:
$ 49.96万 - 项目类别:
Macrophage Phenotype and Impaired Wound Healing
巨噬细胞表型和伤口愈合受损
- 批准号:
8183999 - 财政年份:2011
- 资助金额:
$ 49.96万 - 项目类别:
Macrophage Phenotype and Impaired Wound Healing
巨噬细胞表型和伤口愈合受损
- 批准号:
9024019 - 财政年份:2011
- 资助金额:
$ 49.96万 - 项目类别:
Macrophage Phenotype and Impaired Wound Healing
巨噬细胞表型和伤口愈合受损
- 批准号:
8334595 - 财政年份:2011
- 资助金额:
$ 49.96万 - 项目类别:
Macrophage Phenotype and Impaired Wound Healing
巨噬细胞表型和伤口愈合受损
- 批准号:
8472497 - 财政年份:2011
- 资助金额:
$ 49.96万 - 项目类别:
Macrophage Phenotype and Impaired Wound Healing
巨噬细胞表型和伤口愈合受损
- 批准号:
9080203 - 财政年份:2011
- 资助金额:
$ 49.96万 - 项目类别:
Macrophage Phenotype and Impaired Wound Healing
巨噬细胞表型和伤口愈合受损
- 批准号:
8666769 - 财政年份:2011
- 资助金额:
$ 49.96万 - 项目类别:
相似国自然基金
基于空间代谢流技术探究人参-远志药对通过纠偏单胺类神经递质代谢紊乱治疗阿尔茨海默病的整合作用模式
- 批准号:82304894
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
USP46通过去泛素化修饰RAP80促进同源重组修复的分子机制及其在三阴乳腺癌中的功能研究
- 批准号:82373150
- 批准年份:2023
- 资助金额:48 万元
- 项目类别:面上项目
IL-32通过FAT4介导调控Hippo/YAP信号通路在椎间盘退变中的作用及机制研究
- 批准号:82302737
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
NMN通过肠道活泼瘤胃球菌调控猪胆酸-GLP-1通路改善PCOS的机制研究
- 批准号:32300989
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
徐氏抑肝扶脾方通过ATP/P2X2-TRPV1信号通路调控肠胶质细胞自噬减轻肝郁脾虚型IBS-D神经炎症的机制研究
- 批准号:82305135
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment
PPARg 乙酰化抑制剂预防和治疗糖尿病的临床前验证
- 批准号:
10430186 - 财政年份:2021
- 资助金额:
$ 49.96万 - 项目类别:
Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment
PPARg 乙酰化抑制剂预防和治疗糖尿病的临床前验证
- 批准号:
10225150 - 财政年份:2021
- 资助金额:
$ 49.96万 - 项目类别:
Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment
PPARg 乙酰化抑制剂预防和治疗糖尿病的临床前验证
- 批准号:
10580851 - 财政年份:2021
- 资助金额:
$ 49.96万 - 项目类别: