Role of pregnane x receptor activation on macrophage function and diabetic wound healing

孕烷X受体激活对巨噬细胞功能和糖尿病伤口愈合的作用

• 批准号: 10730438
• 负责人: George E Howell
• 金额: $ 43.95万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730438
• 关键词: Animals; Anti-Bacterial Agents; Antiinflammatory Effect; Binding; Chronic; Clinical; Data; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Disease; Environmental Exposure; Environmental Pollutants; Exposure to; Goals; Human; Hyperglycemia; Infection; Inflammasome; Inflammatory; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Intestines; Kinetics; Knockout Mice; Ligands; Lipopolysaccharides; Liver; Lower Extremity; Macrophage; Macrophage Activation; Mediating; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathogenicity; Patients; Phagocytes; Phagolysosome; Phenotype; Play; Polychlorinated Biphenyls; Receptor Activation; Regimen; Resolution; Risk Factors; Role; Sepsis; Severities; Staphylococcus aureus; Staphylococcus aureus infection; Streptozocin; Survival Rate; Systemic infection; Testing; Therapeutic; Therapeutic Uses; Virulence Factors; Xenobiotic Metabolism; Xenobiotics; bactericide; cell type; chronic wound; clinically relevant; comorbidity; cytokine; diabetes pathogenesis; diabetic; diabetic wound healing; healing; improved; limb amputation; non-diabetic; organochlorine pesticide; pathogen; persistent organic pollutants; pregnane X receptor; pressure; receptor function; response; therapeutic target; type I and type II diabetes; wound; wound healing

Project Summary: While there are a significant number of co-morbidities associated with type 1 and type 2 diabetes (T1D and T2D), one of the more prevalent and severe sequalae of diabetes is diabetic foot ulceration (DFU) with approximately 25% of diabetics developing DFU in their lifetime. Out of all diabetics with DFU, approximately 15-20% of these cases will result in limb amputation due to incomplete healing. Under normal conditions, wound healing is a finely tuned, orchestrated effort by a host of cell types. Amongst these cell types, macrophage function, specifically macrophage plasticity, has been shown to play a critical role in normal wound healing. Thus, alterations in macrophage plasticity and/or function may have a detrimental effect on wound healing. Recent studies have shown that exposure to environmental contaminants, such as organochlorine pesticide metabolites and polychlorinated biphenyls among others, can alter macrophage function. However, the mechanisms governing environmental exposure and other xenobiotic related alterations in macrophage function remain elusive. One potential mechanism governing these exposures is activation of the pregnane x receptor (PXR). The PXR has been widely studied for its role in xenobiotic metabolism due to high levels of expression in the intestines and the liver as well as its ability to bind and become activated by a diverse set of ligands, including commonly used therapeutics and a wide array of environmental contaminants. Thus, the overall hypothesis of this application is that activation of the PXR decreases macrophage plasticity via decreased pro-inflammatory polarization with a corresponding decrease in bactericidal efficacy which will have a deleterious effect on pressure-induced wound healing. We will test this hypothesis in the following three specific aims. In aim 1, we will determine the role of the PXR in macrophage polarization and phagocytic/bactericidal activity in primary macrophages isolated from wild type and PXR knock out (KO) mice under normo- and hyperglycemic conditions. In aim 2 we will determine the effects of PXR activation on pressure-induced wound healing kinetics in both normal and streptozotocin (STZ)-induced diabetic wild type and PXR KO mice. Lastly in aim 3 we will evaluate the ability of the PXR to augment the pathogenicity of clinically relevant diabetic foot ulcer S. aureus isolates. Successful completion of these studies will further delineate the role of the PXR in macrophage function as well as determine if augmentation of PXR function may be deleterious to healing of S. aureus-infected pressure wounds, which is critical given increased S. aureus colonization is positively associated with non-healing DFUs. If PXR plays a deleterious role in wound healing, xenobiotics which activate PXR could be identified as a risk factor for non-healing DFUs to tailor therapeutic regimens in a patient specific manner.

项目概要： 虽然 1 型和 2 型糖尿病存在大量合并症 （T1D 和 T2D），糖尿病最常见和最严重的后遗症之一是糖尿病足溃疡 (DFU)，大约 25% 的糖尿病患者一生中会发生 DFU。在所有糖尿病患者中 DFU，大约有15-20%的病例会因愈合不完全而导致截肢。 在正常情况下，伤口愈合是多种细胞类型精心协调的努力。 在这些细胞类型中，巨噬细胞功能，特别是巨噬细胞可塑性，已被证明 在正常伤口愈合中发挥关键作用。因此，巨噬细胞可塑性和/或功能的改变 可能会对伤口愈合产生不利影响。最近的研究表明，暴露于 环境污染物，例如有机氯农药代谢物和多氯化合物 联苯等可以改变巨噬细胞的功能。然而，治理机制 环境暴露和其他外源性相关的巨噬细胞功能改变仍然存在 难以捉摸。控制这些暴露的一种潜在机制是孕烷 x 受体的激活 （PXR）。由于高水平的 PXR 在外源代谢中的作用已被广泛研究 在肠道和肝脏中的表达及其结合多种物质并被多种物质激活的能力 一组配体，包括常用的治疗方法和各种环境污染物。 因此，本申请的总体假设是 PXR 的激活会减少巨噬细胞 通过减少促炎极化和相应的杀菌作用减少来实现可塑性 这将对压力引起的伤口愈合产生有害影响。我们将测试这个 假设有以下三个具体目标。在目标 1 中，我们将确定 PXR 在以下方面的作用： 从野生动物中分离出的原代巨噬细胞的巨噬细胞极化和吞噬/杀菌活性 正常和高血糖条件下的 PXR 型和 PXR 敲除（KO）小鼠。在目标 2 中，我们将 确定 PXR 激活对正常和正常情况下压力诱导的伤口愈合动力学的影响 链脲佐菌素 (STZ) 诱导的糖尿病野生型和 PXR KO 小鼠。最后，在目标 3 中，我们将评估 PXR 增强临床相关糖尿病足溃疡金黄色葡萄球菌致病性的能力 隔离。这些研究的成功完成将进一步阐明 PXR 在巨噬细胞中的作用 功能并确定 PXR 功能的增强是否可能对链球菌的愈合有害。 金黄色葡萄球菌感染的压力性伤口，鉴于金黄色葡萄球菌定植增加，这一点至关重要 与不愈合的 DFU 相关。如果 PXR 在伤口愈合中发挥有害作用，那么异生素 激活 PXR 可被确定为不愈合 DFU 的危险因素，以调整治疗方案 患者特定的方式。