Reprogramming Macrophages to Improve Vascular Healing in Diabetes

重编程巨噬细胞以改善糖尿病血管愈合

• 批准号: 10426222
• 负责人: Alan Ross Morrison
• 金额: --
• 依托单位: PROVIDENCE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426222
• 关键词: Acute; Aging; American; Amputation; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Area; Binding; Blood Glucose; Blood Vessels; Bone Marrow; Bone Marrow Involvement; Bypass; Caring; Cells; Chronic; Chronic Disease; Complex; Data; Debridement; Dermal; Diabetes Mellitus; Diabetic mouse; Disease; Effectiveness; Endothelial Cells; Experimental Diabetes Mellitus; Fibroblast Growth Factor; Financial Hardship; Genetic Transcription; Goals; Growth Factor; Healthcare Systems; Immune; Impaired healing; Impaired wound healing; Impairment; Individual; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injury; Integrins; Interleukin-1 beta; Lead; Leg Ulcer; Ligation; Limb Salvage; Mechanics; Medical; Modeling; Molecular; Morbidity - disease rate; Mus; NF-kappa B; Nuclear; Operative Surgical Procedures; Osteomyelitis; Pathway interactions; Patients; Perfusion; Peripheral arterial disease; Platelet-Derived Growth Factor; Process; Production; Protein Isoforms; Punch Biopsy; Recovery; Research; Role; STAT3 gene; Signal Transduction; Smooth Muscle Myocytes; Source; Stents; Therapeutic; Thick; Tissues; Ulcer; Up-Regulation; VEGFA gene; Vascular Diseases; Vascular Endothelial Growth Factors; Veterans; angiogenesis; autocrine; base; cell type; chemokine receptor; cytokine; diabetic; femoral artery; healing; health care service utilization; improved; limb ischemia; limb loss; macrophage; mechanical load; military veteran; monocyte; mortality; necrotic tissue; new growth; novel strategies; novel therapeutics; patient subsets; preclinical study; prevent; promoter; response; skin regeneration; standard of care; wound healing

Impaired wound healing in U.S. veterans with diabetes mellitus is a major source of morbidity and mortality as well as a large financial strain on the VA health care system. Current treatment paradigms, including debridement of necrotic tissue, infection control, local ulcer care, mechanical off-loading, and management of blood glucose levels, are modestly effective at best. Despite much research in this area, the critical molecular mechanisms regulating angiogenesis-directed wound healing remain minimally defined. Recently, our group identified an important role for inflammatory macrophage VEGF-A production in consequent angiogenesis/ arteriogenesis required for adequate wound healing. Preliminary data support that VEGF-A expression is increased in “classic inflammatory” macrophages relative to “alternatively activated” or wound healing macrophages. Our preliminary data also identified that macrophage proangiogenic VEGF-A isoform expression is dependent on expression of the potent inflammatory cytokine, IL-1β. Animals with macrophage deletion of IL-1β demonstrated severely impaired macrophage VEGF-A expression and consequent decreases in angiogenesis and arteriogenesis. We have begun to define a mechanistic pathway, whereby autocrine IL-1β- IL-1R signaling promotes transcription of proangiogenic VEGF-A, in part, through activation of NF-kB and STAT3 downstream of the IL-1R. We seek to understand the impact of diabetes on this macrophage proangiogenic mechanism. Mice with experimental diabetes have profound delays in wound healing in a full thickness dermal punch biopsy model and perfusion recovery in a hind limb ischemia model of femoral artery ligation. Isolated macrophages from these diabetic mice demonstrated reduced inflammatory response to IL-1β via reduced expression of IL-1R signaling complex components along with consequent reductions in VEGF-A expression, consistent with the macrophage IL-1β-deletion model. The primary hypothesis is that diabetes mellitus results in reduced macrophage IL-1β-dependent VEGF-A expression with consequent impairment in angiogenesis-dependent wound healing, consistent with the macrophage IL-1β-deletion model. We seek to 1) demonstrate disrupted macrophage IL-1β signaling-dependent proangiogenic VEGF-A isoform expression to be a major mechanism of impaired angiogenesis and wound healing in DM; and 2) validate defective monocyte/macrophage IL-1R signaling-dependent VEGF-A expression from patients with DM who develop chronic lower extremity ulcers despite usual standard of care. By defining inflammatory macrophages as key, early drivers of angiogenesis required for adequate wound healing, our proposed studies support a paradigm shift away from an anti-inflammatory macrophage strategy being required to activate wound healing, allowing for macrophage reprograming strategies that promote appropriate activation of inflammatory macrophages toward consequent angiogenesis-dependent wound healing.

患有糖尿病的美国退伍军人的伤口愈合受损是发病率和死亡率的主要原因 退伍军人管理局医疗保健系统面临巨大的财政压力，包括当前的治疗模式。 坏死组织清创、感染控制、局部溃疡护理、机械卸载和管理 尽管在这一领域进行了大量研究，但关键的分子水平最多只能起到一定的作用。 最近，我们的研究小组对调节血管生成导向的伤口愈合的机制仍知之甚少。 确定了炎症巨噬细胞 VEGF-A 的产生在随后的血管生成中的重要作用/ 伤口充分愈合所需的动脉生成。初步数据支持 VEGF-A 表达。 相对于“替代激活”或伤口愈合，“经典炎症”巨噬细胞增加 我们的初步数据还确定了巨噬细胞促血管生成 VEGF-A 亚型的表达。 依赖于强效炎症细胞因子 IL-1β 巨噬细胞缺失的动物的表达。 IL-1β 表明巨噬细胞 VEGF-A 表达严重受损，从而导致 我们已经开始定义一个机制途径，从而自分泌 IL-1β-。 IL-1R 信号传导促进促血管生成 VEGF-A 的转录，部分是通过激活 NF-kB 和 IL-1R 下游的 STAT3 我们试图了解糖尿病对该巨噬细胞的影响。 促血管生成机制。实验性糖尿病小鼠的伤口完全愈合延迟。 股动脉后肢缺血模型的真皮厚度穿刺活检模型及灌注恢复 从这些糖尿病小鼠中分离出的巨噬细胞显示出对 IL-1β 的炎症反应减少。 通过减少 IL-1R 信号复合物成分的表达以及随之而来的 VEGF-A 的减少 表达，与巨噬细胞 IL-1β 缺失模型一致，主要假设是糖尿病。 导致巨噬细胞 IL-1β 依赖性 VEGF-A 表达减少，从而损害 血管生成依赖性伤口愈合，与巨噬细胞 IL-1β 缺失模型一致，我们寻求 1)。 证明巨噬细胞 IL-1β 信号依赖的促血管生成 VEGF-A 亚型表达受到破坏 是糖尿病血管生成和伤口愈合受损的主要机制；2) 验证缺陷； 糖尿病患者的单核细胞/巨噬细胞 IL-1R 信号依赖性 VEGF-A 表达 尽管采用常规护理标准，但仍存在慢性下肢溃疡 通过将炎症巨噬细胞定义为关键， 伤口充分愈合所需的血管生成的早期驱动因素，我们提出的研究支持一个范例 放弃激活伤口愈合所需的抗炎巨噬细胞策略，从而允许 用于促进炎症巨噬细胞适当激活的巨噬细胞重编程策略 从而促进随后的血管生成依赖性伤口愈合。