Targeting Senescence to Improve Wound Healing in Aging
靶向衰老以改善衰老过程中的伤口愈合
基本信息
- 批准号:10729963
- 负责人:
- 金额:$ 24.3万
- 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:2023-09-01 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectAgingAnti-Inflammatory AgentsApoptosisAttenuatedAwardCDKN2A geneCaringCell AgingCell CommunicationCell ProliferationCellsClinical TrialsCoculture TechniquesCollagenDataData AnalysesDepositionDermalDichloromethylene DiphosphonateEconomicsElderlyExcisionExtracellular MatrixFibroblastsGene ProteinsGeneticGoalsGrowthHeterogeneityHumanImaging TechniquesImpaired healingImpaired wound healingImpairmentLongevityMacrophageMammalsMentorshipModificationMorbidity - disease rateMultiple WoundsMusOperative Surgical ProceduresOrganismPatient riskPatientsPhenotypePhysiciansPlastic SurgeonPredispositionProcessProductionProtein BiosynthesisRegulationResistanceRoleScientistSignal TransductionSkin wound healingSortingSpatial DistributionTestingTherapeuticTimeTissuesTrainingTranslational ResearchUnited StatesWound Infectionacute woundage groupage relatedagedangiogenesisattenuationcell typechronic wounddata visualizationdesignimprovedmiddle agemortalitynecrotic tissuenovelolder patientreconstitutionresponserestorationsenescencesingle-cell RNA sequencingskin woundstressorsubcutaneoustargeted treatmenttissue injurytranscriptomicswoundwound carewound closurewound healingwound response
项目摘要
Impaired or delayed wound healing is a major problem affecting primarily older adults, millions of older adults in
the United States are affected per year. Delayed wound healing increases aged patients’ risk of chronic wounds,
wound infections, and tissue necrosis, resulting in significant morbidity and mortality. Wound care is also a rising
economic problem with an estimated $10 billion annually spent on wound care for older adults. The various
causes for delayed healing of aging ultimately result in perturbations of normal wound healing processes. This
includes a recently discovered wound healing response incorporating cellular senescence, a biologically active
state of permanent growth arrest caused by various stressors like tissue injury. Senescent cells (SnC) that arise
acutely in cutaneous wounds have beneficial effects in wound healing when they are transiently present,
however, specific SnC identities and their associated functions during wound healing have still not been
thoroughly characterized. My preliminary data generated during my GEMSSTAR award confirm a robust and
transient increase in beneficial senescence during excisional wound healing in young (2 month) mice, required
for timely wound resolution. However, my data also demonstrates that in aged (24 month) mice with delayed
wound healing, this acute wound senescence response is significantly attenuated. A similar diminished acute
senescence-like response occurs during aged human wound healing suggesting that attenuation is conserved
between species. To gain better understanding of wound SnCs that benefit wound healing and which are
diminished in aging, my lab has isolated high-expressing p16Ink4a (a common senescence marker) cells from
the wounds of young p16tdTom mice. Preliminary single-cell RNAseq analysis reveals multiple wound cell types
with high p16+ expression during wound healing. A majority are within distinct clusters of fibroblasts (Fb) and
macrophages (Mϕ) with p16+ expression associated with positive regulation of wound healing: p16+ wound Fbs
upregulate genes for protein synthesis and certain collagens while p16+ wound Mϕs are more anti-inflammatory
and promote extracellular matrix deposition with both cell types being more apoptosis-resistant compared to their
respective p16-negative counterparts. As transient senescence is important for optimal wound healing in
younger organisms this project’s goals are to uncover the cellular mechanisms by which specific wound SnCs
positively influence wound healing and determine their roles in delayed healing of aging. I will test the overall
hypothesis that age-related attenuation of beneficial wound SnCs contributes to delayed wound healing in aged
mammals and that restoration of these key wound SnCs can promote more timely wound resolution. The
following Aims are designed to elucidate changes in wound SnCs throughout aging, define their beneficial impact
on wound healing, and provide the therapeutic framework for treatment of delayed healing of aging with
senescence modification.
伤口愈合受损或延迟是主要影响老年人的主要问题,
美国每年都受到影响。伤口愈合延迟会增加老年患者慢性伤口的风险,
伤口感染和组织坏死,导致显著的发病率和死亡率。伤口护理也是一个上升
经济问题,估计每年花费100亿美元用于老年人的伤口护理。的各种
老化的延迟愈合的原因最终导致正常伤口愈合过程的扰动。这
包括最近发现的结合细胞衰老的伤口愈合反应,
由组织损伤等各种压力源引起的永久性生长停滞状态。衰老细胞(SnC)
当它们短暂存在时,在皮肤伤口中的急性毒性对伤口愈合具有有益作用,
然而,特定的SnC身份及其在伤口愈合过程中的相关功能仍然没有被
彻底定性。我在GEMSSTAR奖期间生成的初步数据证实了一个强大的,
年轻(2个月)小鼠切除伤口愈合期间有益衰老的短暂增加,需要
及时解决伤口然而,我的数据也表明,在老年(24个月)小鼠中,
伤口愈合时,这种急性伤口衰老反应显著减弱。一个类似的减少急性
在老年人伤口愈合期间发生衰老样反应,表明衰减是保守的
物种之间。为了更好地了解有利于伤口愈合的伤口SnC,
我的实验室已经分离出高表达p16Ink4a(一种常见的衰老标志物)的细胞,
p16tdTom幼鼠的伤口初步单细胞RNAseq分析揭示多种伤口细胞类型
p16+在伤口愈合过程中表达增高。大多数在成纤维细胞(Fb)的不同簇内,
具有与伤口愈合的正调节相关的p16+表达的巨噬细胞(M β):p16+伤口Fbs
上调蛋白质合成和某些胶原蛋白的基因,而p16+伤口M细胞更具抗炎性
并促进细胞外基质沉积,两种细胞类型与它们的
相应的p16阴性对应物。由于短暂的衰老对于创伤的最佳愈合是重要的,
该项目的目标是揭示特定伤口SnCs的细胞机制,
积极影响伤口愈合,并确定其在延迟老化愈合中的作用。我将测试整体
有益伤口SnCs的年龄相关衰减有助于老年人伤口愈合延迟的假设
哺乳动物和这些关键伤口SnC的恢复可以促进更及时的伤口解决。的
以下目的旨在阐明伤口SnC在整个老化过程中的变化,确定其有益影响
对伤口愈合,并提供治疗框架,治疗延迟愈合的老化,
衰老修饰
项目成果
期刊论文数量(0)
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Daniel Sam Roh其他文献
Daniel Sam Roh的其他文献
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{{ truncateString('Daniel Sam Roh', 18)}}的其他基金
Role of Senescence in the Impaired Wound Healing of Aging
衰老在衰老伤口愈合受损中的作用
- 批准号:
10027701 - 财政年份:2020
- 资助金额:
$ 24.3万 - 项目类别:
Role of Senescence in the Impaired Wound Healing of Aging
衰老在衰老伤口愈合受损中的作用
- 批准号:
10251307 - 财政年份:2020
- 资助金额:
$ 24.3万 - 项目类别:
Homeostatic Roles of Connexin43 in Response to DNA Damage
Connexin43 在 DNA 损伤反应中的稳态作用
- 批准号:
8215633 - 财政年份:2010
- 资助金额:
$ 24.3万 - 项目类别:
Homeostatic Roles of Connexin43 in Response to DNA Damage
Connexin43 在 DNA 损伤反应中的稳态作用
- 批准号:
8044043 - 财政年份:2010
- 资助金额:
$ 24.3万 - 项目类别:
Homeostatic Roles of Connexin43 in Response to DNA Damage
Connexin43 在 DNA 损伤反应中的稳态作用
- 批准号:
7805954 - 财政年份:2010
- 资助金额:
$ 24.3万 - 项目类别:
Homeostatic Roles of Connexin43 in Response to DNA Damage
Connexin43 在 DNA 损伤反应中的稳态作用
- 批准号:
8403696 - 财政年份:2010
- 资助金额:
$ 24.3万 - 项目类别:
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