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.

抽象的 持续未解决的炎症会损害糖尿病伤口的愈合。伤口的功能和命运 单核细胞/巨噬细胞 (mφ) 是伤口炎症结果的关键。该提案建立在 源自活的功能性伤口巨噬细胞 (wmφ) 和慢性伤口液的观察结果 然后使用实验模型进一步开发患者的伤口。鉴于目前的模糊性 巨噬细胞命名法，并提出 wmφ 与 M1/M2 命名法的不匹配，对于这个建议，我们 根据促炎 (mphiinf) 或促消退/愈合 (mphiheal) 功能状态对 wmphi 进行分类。我们 据报道，i) 成功的 wmphi 胞吞作用 (Eff) 有助于解决炎症； ii) 胞吞作用 糖尿病伤口的 wmφ 严重受损 (Efflo)，导致未解决的炎症，以及 iii) Efflo 的校正 重组 MFG-E8 (rMFG-E8) 在糖尿病伤口的 wmφ 中可消除炎症并促进伤口 康复。我们的实验室率先报道了miRNA-21在伤口调节中的关键作用 炎。我们最近报告了一个新范式的框架，提出 wmψ 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 描述这一范式的重点是两个新颖的方面：(i) miR 货物在细胞外捕获 伤口炎症部位的囊泡（EV）决定 wm 的命运和炎症状态； (二) 在糖尿病伤口炎症部位，miR 被表观遗传沉默（甲基化），使得 炎症持续存在。提出以下三个目标： 目标 1：测试 miR-21 和胞吞作用至关重要 伤口部位单核细胞/巨噬细胞命运的决定因素。 §1.1 从 mphiinf 转换而来的 wmphi 的唯一子集  mΦF;封装在伤口部位细胞外囊泡 (EV) 中的 miR-21 被递送到 wmphi 以引起这种 转换。 §1.2 wmphi 的另一个子集经历 mphiinfmphiheal；该子集在分辨率中起着至关重要的作用 伤口炎症和愈合。目标 2：确定糖尿病如何改变导致 wmphi 的命运 治愈脱轨。 §2.1 糖尿病引起 wmphi (miR-21lo) 中 miR-21 表观遗传沉默。这样的 赤字与受损的胞吞作用 (Efflo) 相结合，使 wmphi 停滞在 mphiinf 中； §2.2 在糖尿病 wmφ 中，校正 miR-21 和胞吞作用促进糖尿病 mphiinfmphiheal/mphiF 恢复愈合。新型巨噬细胞靶向 脂质纳米颗粒 (LNPmφ) 将纠正糖尿病 miR-21lo。目标 3：研究活体 wmφ 和伤口边缘组织活检 从患者的糖尿病伤口中分离出来，测试是否： §3.1 wmΦ 到 mΦF（或 mΦheal）的转变是 在控制不佳的糖尿病患者 (HbA1c>9) 中受到损害，其中 miR-21 在表观遗传学上是沉默的； §3.2 修正 miR-21 和胞吞作用将糖尿病 wmφ 从 mφinfmφheal/mφF 推进。

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