Macrophage Phenotype and Impaired Wound Healing

巨噬细胞表型和伤口愈合受损

• 批准号: 9024019
• 负责人: TIMOTHY J KOH
• 金额: $ 54.36万
• 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 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9024019
• 关键词: Adult; Antidiabetic Drugs; Basic Science; Biochemical; Biological Markers; Biomechanics; Blocking Antibodies; Bone Marrow; Cell surface; Cells; Characteristics; Chronic; Clinical; Clinical Trials; Clinical Trials Design; Data; Development; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Double-Blind Method; Exhibits; Flow Cytometry; Funding; Generations; Glyburide; Goals; Grant; Healed; Health; Human; Image Cytometry; Impaired wound healing; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-1 beta; Knowledge; Laboratories; Lead; Link; Measurement; Monitor; Mus; Myelopoiesis; Nuclear Orphan Receptor; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Placebos; Production; Publishing; Quality of life; Randomized; Randomized Clinical Trials; Reporting; Research; Resolution; Role; Selection for Treatments; Signal Transduction; Site; Skin; Testing; Topical application; Translating; Translations; Travel; Treatment Cost; United States; United States National Institutes of Health; Wound Healing; assay development; chronic wound; diabetic; diabetic patient; healing; improved; in vivo imaging; inhibitor/antagonist; macrophage; monocyte; mouse model; programs; public health relevance; research study; response; socioeconomics; targeted treatment; translational study; wound

 DESCRIPTION (provided by applicant): Chronic wounds associated with diabetes are a burgeoning health problem in the United States. A common characteristic of these poorly healing wounds is a persistent inflammatory response, with accumulation of pro-inflammatory macrophages. The central hypothesis of this proposal is that diabetes induces overproduction of pro-inflammatory monocytes and reduces levels of pro-healing monocytes that each contribute to the poor healing responses in diabetic wounds. We propose a translational study involving both mouse models and human patients with three Specific Aims: in the first Aim, we will determine whether sustained activity of the NLRP3 inflammasome/IL-1β pathway results in overproduction of pro-inflammatory monocytes and impaired healing in diabetes. In the second Aim, we will determine whether impaired activity of Nur77 reduces levels of pro-healing monocytes contributing to impaired healing in diabetes. In the third Aim, we will perform an informative pilot double-blinded, randomized clinical trial to determine whether topical treatment with glyburide can modulate monocyte subsets prior to and/or after wound infiltration and improve healing in diabetes. The proposed experiments will improve knowledge of the role of monocyte subsets during impaired healing in diabetic mice and humans along with cell-intrinsic and cell-extrinsic mechanisms that regulate production of these cells. The impact of these studies lies in the initial translation to a therapy that targets monocyte subsets in diabetic patients to induce resolution of inflammation and stimulate healing responses in hard-to-heal wounds. In addition, the studies could lead to development of assays that involve monitoring blood monocyte subsets as cellular biomarkers to aid in the selection of treatment options for diabetic patients with chronic wounds.

 描述（由申请人提供）：与糖尿病相关的慢性伤口是美国一个新兴的健康问题。这些愈合不良的伤口的一个共同特征是持续的炎症反应，并伴有促炎巨噬细胞的积累。该提议的中心假设是，糖尿病会导致促炎单核细胞的过度产生，并降低促愈合单核细胞的水平，而这两种因素都会导致糖尿病伤口的愈合反应不佳。我们提出了一项涉及小鼠模型和人类患者的转化研究，具有三个具体目标：在第一个目标中，我们将确定 NLRP3 炎性体/IL-1β 途径的持续活性是否会导致促炎性单核细胞过度产生并损害糖尿病的愈合。在第二个目标中，我们将确定 Nur77 活性受损是否会降低促愈合单核细胞的水平，从而导致糖尿病愈合受损。在第三个目标中，我们将进行一项信息丰富的双盲、随机临床试验，以确定格列本脲局部治疗是否可以在伤口浸润之前和/或之后调节单核细胞亚群并改善糖尿病的愈合。拟议的实验将提高对单核细胞亚群在糖尿病小鼠和人类愈合受损过程中的作用以及调节这些细胞产生的细胞内在和细胞外在机制的了解。这些研究的影响在于初步转化为一种针对糖尿病患者单核细胞亚群的疗法，以诱导炎症消退并刺激难以愈合伤口的愈合反应。此外，这些研究可能会导致开发一些检测方法，包括监测血液单核细胞亚群作为细胞生物标志物，以帮助选择患有慢性伤口的糖尿病患者的治疗方案。