Macrophage Phenotype and Impaired Wound Healing

巨噬细胞表型和伤口愈合受损

• 批准号: 8666769
• 负责人: TIMOTHY J KOH
• 金额: $ 39.2万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666769
• 关键词: Address; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Biopsy; Caspase-1; Cells; Characteristics; Chronic; Cleaved cell; Clinical Treatment; Collagen; Data; Deposition; Development; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Environment; Excision; Exhibits; Future; Goals; Healed; Health; Impaired wound healing; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Knowledge; Learning; Monitor; Mus; Nature; Pathway interactions; Patients; Peptide Hydrolases; Peroxisome Proliferator-Activated Receptors; Phenotype; Quality of life; Regulation; Research; Resolution; Role; Selection for Treatments; Skin; Testing; Therapeutic; Tissues; Translational Research; Treatment Cost; United States; Venous Insufficiency; Wound Healing; angiogenesis; cytokine; diabetic; diabetic patient; diabetic wound healing; effective therapy; healing; improved; in vitro Model; inhibitor/antagonist; insight; killings; macrophage; non-diabetic; novel therapeutic intervention; pathogen; pressure; receptor; research study; response; socioeconomics; therapy development; translational study; wound

DESCRIPTION (provided by applicant): Chronic wounds associated with diabetes represent a significant health problem in the United States. Despite the socioeconomic impact of these poorly healing wounds, the underlying causes of impaired healing are not well understood and effective treatments remain elusive. Chronic wounds exhibit a dysregulated inflammatory response, with persistent accumulation of macrophages and inflammatory cytokines. We propose a translational study to address our central hypothesis that an impaired switch from pro-inflammatory to pro-healing macrophage phenotypes contributes to the poor healing responses in diabetic wounds and that inducing macrophages to switch phenotype will improve healing. The study is composed of three Specific Aims: in the first Aim, we will determine whether sustained activity of the inflammasome, a critical control point in the regulation of inflammation, promotes a bias towards the pro-inflammatory macrophage phenotype in wounds of diabetic mice. In the second Aim, we will determine whether impaired activity of the anti-inflammatory peroxisome proliferator- activated receptor-3 pathway blocks the switch from pro-inflammatory to pro-healing Mp phenotypes in wounds of diabetic mice. In the third Aim, we will determine whether the diabetic wound environment impairs the switch from pro-inflammatory to pro-healing Mp phenotypes, which impairs healing of chronic wounds. The proposed experiments will improve knowledge of the role and regulation of macrophage phenotypes in the impaired healing of diabetic wounds. If the experiments support our central hypothesis, future studies will be focused on developing therapies that modulate macrophage phenotype in chronic wounds to induce resolution of inflammation and stimulate healing responses in these hard-to-heal wounds. In addition, we will determine whether monitoring Mp phenotype in chronic wounds can be used to aid in the selection of treatment options that are currently available for targeting inflammation.

描述（由申请人提供）：在美国，与糖尿病相关的慢性伤口是一个严重的健康问题。尽管这些愈合不良的伤口的社会经济影响，愈合受损的根本原因还没有得到很好的理解，有效的治疗仍然难以捉摸。慢性伤口表现出失调的炎症反应，伴随巨噬细胞和炎性细胞因子的持续积累。我们提出了一个转化研究，以解决我们的中心假设，即从促炎到促愈合巨噬细胞表型的受损转换有助于糖尿病伤口的不良愈合反应，诱导巨噬细胞转换表型将改善愈合。该研究由三个特定目的组成：在第一个目的中，我们将确定炎症体（炎症调节中的关键控制点）的持续活性是否促进糖尿病小鼠伤口中促炎巨噬细胞表型的偏向。在第二个目标中，我们将确定抗炎过氧化物酶体增殖物激活受体-3途径的活性受损是否阻断糖尿病小鼠伤口中从促炎表型到促愈合表型的Mp转换。在第三个目标中，我们将确定糖尿病伤口环境是否损害从促炎到促愈合Mp表型的转换，这损害慢性伤口的愈合。拟议的实验将提高知识的作用和调节巨噬细胞表型在受损愈合的糖尿病伤口。如果实验支持我们的中心假设，未来的研究将集中在开发调节慢性伤口中巨噬细胞表型的疗法，以诱导炎症消退并刺激这些难以愈合的伤口的愈合反应。此外，我们将确定监测慢性伤口中的Mp表型是否可用于帮助选择目前可用于靶向炎症的治疗方案。