Notch Signaling Dictates CD4+T cell Activation in Diabetic Wounds
Notch 信号传导决定糖尿病伤口中 CD4 T 细胞的激活
基本信息
- 批准号:10313485
- 负责人:
- 金额:$ 7.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAmputationAnimal ModelAnimalsCD4 Positive T LymphocytesCellsChronicDataData AnalysesDiabetes MellitusEnsureFailureFoundationsFunctional disorderGeneticGoalsHealthcare SystemsHumanImmune responseImpaired healingImpaired wound healingInflammationInflammatoryInflammatory ResponseInjuryLeadLigandsMediatingMethodsMolecularMusMyeloid CellsNon-Insulin-Dependent Diabetes MellitusNormal tissue morphologyPathologicPatientsPharmacologyPhenotypePlayReceptor ActivationReceptor SignalingRegulationRegulatory T-LymphocyteResearch DesignRoleScientistSignal PathwaySignal TransductionSurgeonT-Cell ActivationT-LymphocyteTechniquesTestingTherapeuticTissuesTrainingTweensUnited StatesWound modelscostdiabeticdiabetic ulcerdiabetic wound healingexperimental studyhealingimprovedmacrophagemanmortalitynew therapeutic targetnotch proteinnovelreceptorsuccesstherapeutic targettissue repairwoundwound healing
项目摘要
PROJECT SUMMARY
Secondary complications of type 2 diabetes (T2D), including impaired wound healing,
are increasing, and therapeutic options remain limited and only marginally effective. Failure
of wound healing in T2D patients represents the most common cause of amputation in the
US and has an a 5-year mortality rate of 50%. Thus, a critical need exists for understanding the
pathophysiology of T2D woundsto identify novel mechanisms that can be therapeutically targeted.
In normal wound healing, a coordinated immune response between macrophages (Mφs), and
CD4+T cells is critical for a controlled inflammatory response and tissue repair. Although the
molecular mechanisms that dictate these interactions following injury are not well understood, our
group and others have identified that Notch signaling plays a critical role in wound healing.
Depending on the specific ligand-receptor interactions, CD4+T cell activation results in
differentiation into a specific T cell phenotype. It has been observed that CD4+T regulatory (Treg)
cells are critical to ensure normal tissue repair, while TH17 phenotypes promote excess
inflammation and impair healing; however, the mechanisms that control CD4+T cell activation in
wound tissue are unknown. Our preliminary data show that increased Notch signaling between
Mφs/CD4+T cells in diabetes can lead to increased TH17, decreased Tregs, excess inflammation
and pathologic healing. While the precise regulation of Treg/TH17 differentiation during wound
repair is unclear, our preliminary data identify that the Notch ligand, DLL4, is upregulated in
diabetic wound Mφs, and that DLL4 interactions with the Notch 2 receptor on CD4+T cells
promotes an inflammatory TH17 phenotype as opposed to Treg differentiation. We hypothesize
that DLL4-mediated Notch receptor signaling in diabetic wounds polarizes CD4+T cells in
the wound towards TH17 and promotes chronic inflammation and non-healing and that
local blockade of DLL4 will decrease inflammation and improve healing in diabetic murine
wounds. To test our hypotheses, we will pursue the following Specific Aims:
1) To identify the role of Notch 2 receptor activation on Treg/TH17 differentiation in acute
and chronic diabetic murine wound models.
2) To determine if genetic or local therapeutic blockage of DLL4 ligand limits TH17
differentiation, decreases inflammation and improves diabetic wound repair.
项目摘要
2型糖尿病(T2 D)的继发性并发症,包括伤口愈合受损,
越来越多,治疗选择仍然有限,只有轻微的效果。失败
2型糖尿病患者伤口愈合的最常见原因是截肢。
美国,5年死亡率为50%。因此,迫切需要了解
T2 D伤口的病理生理学,以确定可以治疗靶向的新机制。
在正常的伤口愈合中,巨噬细胞(Mφ)和
CD 4 +T细胞对于受控的炎症反应和组织修复至关重要。虽然
损伤后决定这些相互作用的分子机制还没有很好地理解,
小组和其他人已经确定Notch信号在伤口愈合中起关键作用。
根据特定的配体-受体相互作用,CD 4 +T细胞活化导致
分化成特定的T细胞表型。已经观察到,CD 4 +T调节性(Treg)
细胞是确保正常组织修复的关键,而TH 17表型促进过量的
炎症和损伤愈合;然而,控制CD 4 +T细胞活化的机制,
伤口组织不明我们的初步数据表明,增加Notch信号之间,
糖尿病患者的Mφs/CD 4 +T细胞可导致TH 17升高、T细胞减少、炎症反应过度
和病理愈合。虽然创伤过程中Treg/TH 17分化的精确调节
修复尚不清楚,我们的初步数据表明,Notch配体DLL 4在细胞内表达上调。
DLL 4与CD 4 +T细胞上的Notch 2受体相互作用
促进炎性TH 17表型,而不是Treg分化。我们假设
DLL 4介导的Notch受体信号在糖尿病伤口中极化CD 4 +T细胞,
伤口朝向TH 17并促进慢性炎症和不愈合,
DLL 4的局部阻断将减少糖尿病小鼠中的炎症并改善愈合
伤口为了验证我们的假设,我们将追求以下具体目标:
1)为了鉴定Notch 2受体活化对急性白血病中Treg/TH 17分化的作用,
和慢性糖尿病鼠伤口模型。
2)确定DLL 4配体的遗传或局部治疗阻断是否限制了TH 17
分化,减少炎症并改善糖尿病伤口修复。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Emily Caitlin Barrett其他文献
Emily Caitlin Barrett的其他文献
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{{ truncateString('Emily Caitlin Barrett', 18)}}的其他基金
Notch Signaling Dictates CD4+T cell Activation in Diabetic Wounds
Notch 信号传导决定糖尿病伤口中 CD4 T 细胞的激活
- 批准号:
10442409 - 财政年份:2021
- 资助金额:
$ 7.31万 - 项目类别:
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