Mechanisms Underlying Impaired Diabetic Wound Healing

糖尿病伤口愈合受损的机制

• 批准号: 10205045
• 负责人: Sashwati Roy
• 金额: $ 39.38万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10205045
• 关键词: Affect; Animals; Anti-Inflammatory Agents; Apoptotic; Biopsy; COL1A1 gene; Cells; Cues; Diabetes Mellitus; Encapsulated; Environment; Epigenetic Process; Exhibits; Experimental Models; Fibroblasts; Glycosylated hemoglobin A; Goals; Hydrogels; Impairment; Inflammation; Inflammatory; Intervention; Knowledge; Laboratories; Liquid substance; MicroRNAs; Nature; Nomenclature; Outcome; Pathway interactions; Patients; Play; Process; Recombinants; Regulation; Reporting; Resolution; Rest; Role; S100A4 gene; Site; Societies; Testing; Tissues; United States; Vertebral column; base; chronic wound; clinically relevant; clinically significant; diabetes management; diabetic; diabetic ulcer; diabetic wound healing; epigenetic silencing; extracellular vesicles; healing; improved; innovation; lipid nanoparticle; macrophage; monocyte; novel; novel strategies; peer; skin wound; wound; wound healing

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 mϕinfmϕheal; 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 mϕinfmϕheal/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 mϕinfmϕheal/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mϕInfmϕHear；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mϕInfmϕHear/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mϕInfmϕHear/mϕF.

项目成果

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: Nanomedicine : nanotechnology, biology, and medicine
• 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: ACS nano
• 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: Bioengineering (Basel, Switzerland)
• 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: The Journal of investigative dermatology
• 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: Annals of surgery
• 影响因子: 9