Mechanisms Underlying Impaired Diabetic Wound Healing
糖尿病伤口愈合受损的机制
基本信息
- 批准号:10205045
- 负责人:
- 金额:$ 39.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimalsAnti-Inflammatory AgentsApoptoticBiopsyCOL1A1 geneCellsCuesDiabetes MellitusEncapsulatedEnvironmentEpigenetic ProcessExhibitsExperimental ModelsFibroblastsGlycosylated hemoglobin AGoalsHydrogelsImpairmentInflammationInflammatoryInterventionKnowledgeLaboratoriesLiquid substanceMicroRNAsNatureNomenclatureOutcomePathway interactionsPatientsPlayProcessRecombinantsRegulationReportingResolutionRestRoleS100A4 geneSiteSocietiesTestingTissuesUnited StatesVertebral columnbasechronic woundclinically relevantclinically significantdiabetes managementdiabeticdiabetic ulcerdiabetic wound healingepigenetic silencingextracellular vesicleshealingimprovedinnovationlipid nanoparticlemacrophagemonocytenovelnovel strategiespeerskin woundwoundwound healing
项目摘要
ABSTRACT
Persistent unresolved inflammation impairs diabetic wound healing. The function and fate of wound
monocyte/macrophages (mϕ) hold the key to the outcome of wound inflammation. This proposal builds on
observations originating from live functional wound macrophages (wmϕ) and wound fluid derived from chronic
wounds of patients which were then developed further using experimental models. Given current ambiguity in
macrophage nomenclature, and proposed misfit of wmϕ with the M1/M2 nomenclature, for this proposal we
classify wmϕ based on the pro-inflammatory (mϕinf) or pro-resolution/healing (mϕheal) functional states. We
have reported that i) successful wmϕ efferocytosis (Eff) helps resolve inflammation; and ii) Efferocytosis
severely impaired (Efflo) in wmϕ of diabetic wounds causing unresolved inflammation, and iii) correction of Efflo
with recombinant MFG-E8 (rMFG-E8) in wmϕ of diabetic wounds resolves inflammation and promotes wound
healing. Our laboratory was the first to report a critical role of miRNA-21 in the regulation of wound
inflammation. We recently reported the framework of a new paradigm proposing that the plasticity of wmϕ at
the wound-site is a major determinant of the state of wound inflammation. The current proposal seeks to
characterize this paradigm with emphasis on two novel aspects: (i) that miR cargo captured in extracellular
vesicles (EVs) at the site of wound inflammation determine the fate of wmϕ and state of inflammation; and (ii)
that at the site of diabetic wound inflammation miR is epigenetically silenced (methylated) such that
inflammation persists. The following three aims are proposed: Aim 1: Test miR-21 and efferocytosis as critical
determinants of monocyte/macrophage fate at the wound-site. §1.1 A unique subset of wmϕ convert from mϕinf
mϕF; miR-21 encapsulated in wound-site extracellular vesicles (EV) are delivered to wmϕ to cause such
conversion. §1.2 Another subset of wmϕ undergoes mϕinfmϕheal; this subset plays a critical role in resolution
of wound inflammation and healing. Aim 2: Determine how diabetes redirects the fate of wmϕ causing
derailment of healing. §2.1 Diabetic conditions cause miR-21 epigenetic silencing in wmϕ (miR-21lo). Such
deficit, in combination with impaired efferocytosis (Efflo), stalls wmϕ in mϕinf; §2.2 In diabetic wmϕ, correction of
miR-21 and efferocytosis advances diabetic mϕinfmϕheal/mϕF resuming healing. Novel macrophage-targeted
lipid nanoparticle (LNPmφ) will correct diabetic miR-21lo. Aim 3: Study live wmϕ and wound-edge tissue biopsies
isolated from diabetic wounds of patients testing whether: §3.1 transition of wmϕ to mϕF (or mϕheal) is
compromised in poorly controlled diabetics (HbA1c>9) where miR-21 is epigenetically silent; §3.2 correction of
miR-21 and efferocytosis advances diabetic wmϕ from mϕinfmϕheal/mϕF.
摘要
持续未消退的炎症损害糖尿病伤口的愈合。伤口的功能和命运
单核/巨噬细胞(m-ϕ)是决定创面炎症转归的关键细胞。这项建议的基础是
功能性创面活巨噬细胞(Wm-ϕ)和慢性创面分泌液的观察
患者的伤口,然后使用实验模型进一步发展。中的当前歧义
巨噬细胞命名法,并建议Wmϕ与M1/M2命名法不匹配,对于这一建议,我们
根据促炎(mϕInf)或促解决/修复(mϕHear)功能状态对Wmϕ进行分类。我们
已经报道:i)成功的Wmϕ泡沫化(Eff)有助于消炎;以及ii)Effercell
糖尿病创面Wmϕ严重受损(EFLO),导致未消退的炎症,以及III)纠正EFLO
重组MFG-E8(rMFG-E8)在糖尿病创面Wmϕ中消炎促进创面生长
治愈。我们实验室首次报道了miRNA-21在伤口调节中的关键作用。
发炎。我们最近报告了一个新范式的框架,提出Wmϕ的可塑性在
伤口部位是伤口炎症状态的主要决定因素。目前的提案旨在
描述这一范例,强调两个新的方面:(I)在细胞外捕获的miR货物
创面炎症部位的小泡(EVS)决定Wmϕ的命运和炎症状态;
在糖尿病创面炎症部位,miR在表观遗传上被沉默(甲基化),从而
炎症持续存在。提出了以下三个目标:目标1:以检测miR-21和泡沫化为关键
伤口处单核/巨噬细胞命运的决定因素。§1.1 Wmϕ从mϕInf转换的唯一子集
mϕF;miR-21被包裹在创面细胞外小泡(EV)中,输送到Wmϕ以引起
转换。§1.2 Wmϕ的另一个子集经历mϕInfmϕHear;这个子集在解析中起着关键作用
伤口发炎和愈合。目标2:确定糖尿病如何改变导致Wmϕ的命运
治愈的脱轨。§2.1糖尿病导致Wmϕ中miR-21表观遗传沉默(miR-21lo)。是这样的
缺陷,加上泡腾功能受损(EFLO),使Wmϕ在mϕInf中停滞不前;§2.2在糖尿病Wmϕ中,更正
MIR-21和泡腾促进糖尿病mϕInfmϕHear/mϕF恢复愈合。新型巨噬细胞靶向研究
脂质纳米粒(LNPM-φ)可纠正糖尿病MIR-21LO。目的3:研究活体Wmϕ和创缘组织活检
从糖尿病患者的伤口中分离出来测试:§3.1 Wmϕ到mϕF(或mϕHear)的转变是否
控制不佳的糖尿病患者的损害(HbA1c&>9),其中miR-21是表观遗传沉默的;§3.2更正
MIR-21和泡泡细胞吞噬促进糖尿病Wmϕ来自mϕInfmϕHear/mϕF.
项目成果
期刊论文数量(24)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Neurogenic tissue nanotransfection in the management of cutaneous diabetic polyneuropathy.
- DOI:10.1016/j.nano.2020.102220
- 发表时间:2020-08
- 期刊:
- 影响因子:0
- 作者:Roy S;Sen CK;Ghatak S;Higuita-Castro N;Palakurti R;Nalluri N;Clark A;Stewart R;Gallego-Perez D;Prater DN;Khanna S
- 通讯作者:Khanna S
Exosome-Mediated Crosstalk between Keratinocytes and Macrophages in Cutaneous Wound Healing.
- DOI:10.1021/acsnano.0c03064
- 发表时间:2020-10-27
- 期刊:
- 影响因子:17.1
- 作者:Zhou X;Brown BA;Siegel AP;El Masry MS;Zeng X;Song W;Das A;Khandelwal P;Clark A;Singh K;Guda PR;Gorain M;Timsina L;Xuan Y;Jacobson SC;Novotny MV;Roy S;Agarwal M;Lee RJ;Sen CK;Clemmer DE;Ghatak S
- 通讯作者:Ghatak S
Collagen in Wound Healing.
- DOI:10.3390/bioengineering8050063
- 发表时间:2021-05-11
- 期刊:
- 影响因子:0
- 作者:Mathew-Steiner SS;Roy S;Sen CK
- 通讯作者:Sen CK
Oncostatin M Improves Cutaneous Wound Re-Epithelialization and Is Deficient under Diabetic Conditions.
- DOI:10.1016/j.jid.2021.04.039
- 发表时间:2022-03
- 期刊:
- 影响因子:0
- 作者:Das A;Madeshiya AK;Biswas N;Ghosh N;Gorain M;Rawat A;Mahajan SP;Khanna S;Sen CK;Roy S
- 通讯作者:Roy S
Pseudomonas Aeruginosa Theft Biofilm Require Host Lipids of Cutaneous Wound.
- DOI:10.1097/sla.0000000000005252
- 发表时间:2023-03-01
- 期刊:
- 影响因子:9
- 作者:
- 通讯作者:
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Sashwati Roy其他文献
Sashwati Roy的其他文献
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{{ truncateString('Sashwati Roy', 18)}}的其他基金
Tissue reprogramming in diabetic wound healing
糖尿病伤口愈合中的组织重编程
- 批准号:
10936105 - 财政年份:2023
- 资助金额:
$ 39.38万 - 项目类别:
Tissue reprogramming in diabetic wound healing
糖尿病伤口愈合中的组织重编程
- 批准号:
10224448 - 财政年份:2021
- 资助金额:
$ 39.38万 - 项目类别:
Tissue reprogramming in diabetic wound healing
糖尿病伤口愈合中的组织重编程
- 批准号:
10382439 - 财政年份:2021
- 资助金额:
$ 39.38万 - 项目类别:
ZEISS PALM MicroBeam IV module Rel 4.2
ZEISS PALM MicroBeam IV 模块 Rel 4.2
- 批准号:
8052425 - 财政年份:2011
- 资助金额:
$ 39.38万 - 项目类别:
Mechanisms underlying impaired diabetic wound healing
糖尿病伤口愈合受损的机制
- 批准号:
8004785 - 财政年份:2009
- 资助金额:
$ 39.38万 - 项目类别:
Mechanisms underlying impaired diabetic wound healing
糖尿病伤口愈合受损的机制
- 批准号:
7580899 - 财政年份:2008
- 资助金额:
$ 39.38万 - 项目类别:
Mechanisms underlying impaired diabetic wound healing
糖尿病伤口愈合受损的机制
- 批准号:
8019532 - 财政年份:2008
- 资助金额:
$ 39.38万 - 项目类别:
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