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.

项目总结: