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： 虽然有大量的合并症与1型和2型糖尿病相关， (T1D和T2 D），糖尿病的更普遍和严重的后遗症之一是糖尿病足溃疡 (DFU)大约25%的糖尿病患者在其一生中发展DFU。在所有糖尿病患者中， DFU，其中大约15-20%的病例会因愈合不完全而导致肢体截肢。 在正常情况下，伤口愈合是一个精心调整，精心策划的努力，由一个主机的细胞类型。 在这些细胞类型中，巨噬细胞的功能，特别是巨噬细胞的可塑性，已被证明是 在正常的伤口愈合中起着关键作用。因此，巨噬细胞可塑性和/或功能的改变 可能对伤口愈合有不利影响。最近的研究表明， 环境污染物，如有机氯农药代谢物和多氯 其中，联苯可改变巨噬细胞功能。然而，管理机制 环境暴露和其他与异生物质相关的巨噬细胞功能改变仍然存在 难以捉摸。一个潜在的机制，管理这些曝光是激活的α-羟色胺x受体 （PXR）. PXR由于其在异生物质代谢中的作用而被广泛研究， 在肠道和肝脏中的表达，以及其结合并被多种 一组配体，包括常用的治疗剂和广泛的环境污染物。 因此，本申请的总体假设是PXR的活化减少巨噬细胞的凋亡。 可塑性通过减少促炎性极化与相应的减少杀菌 这将对压力诱导的伤口愈合产生有害影响。我们将测试这个 假设在以下三个具体目标。在目标1中，我们将确定PXR的作用， 从野生型分离的原代巨噬细胞中的巨噬细胞极化和吞噬/杀菌活性 型和PXR敲除（KO）小鼠。在目标2中， 确定PXR激活对正常和创伤患者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致病性的能力。金黄色 分离株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。 功能以及确定PXR功能的增强是否可能对S. 金黄色葡萄球菌感染的压力伤口，这是至关重要的增加S。金黄色葡萄球菌定植阳性 与非愈合DFU相关。如果PXR在伤口愈合中起有害作用， 激活PXR可以被确定为非愈合DFU的风险因素，以调整治疗方案， 患者的具体方式。