Targeting the CHRNA7 Receptor to Modulate Wound Antimicrobial Responses

靶向 CHRNA7 受体调节伤口抗菌反应

• 批准号: 9896364
• 负责人: Katherine Amanda Radek
• 金额: $ 20.13万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896364
• 关键词: Acetylcholine; Address; Agonist; Anti-Inflammatory Agents; Antibiotics; Bacteremia; Bacterial Infections; Cells; Chemotactic Factors; Communication; Data; Defect; Diabetes Mellitus; Disease; Economic Burden; Elderly; Epithelial; Epithelium; Estrogens; Excision; Female; Health; Healthcare; Host Defense; Human; Immune; Immune response; Impairment; In Vitro; Incidence; Infection; Infection prevention; Infectious Skin Diseases; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Knowledge; Ligands; Mediating; Mission; Modality; Modeling; Morbidity - disease rate; Mus; Nicotine; Nicotinic Receptors; Outcome; Oxazolone; Pathologic; Pathway interactions; Patients; Peptides; Phagocytes; Pharmacology; Phenotype; Physiological; Play; Predisposition; Preventive measure; Production; Public Health; Regulation; Reporting; Research; Role; Sepsis; Severities; Sex Differences; Signal Pathway; Signal Transduction; Site; Skin; Skin wound healing; Small Interfering RNA; Smoker; Staphylococcus aureus; Staphylococcus aureus infection; Stimulus; TLR2 gene; Testing; Tissues; Toll-like receptors; Topical application; Tumor-infiltrating immune cells; United States National Institutes of Health; Wild Type Mouse; Woman; Wound Infection; antimicrobial; antimicrobial peptide; care burden; chemokine; cholinergic; cytokine; diabetic wound healing; immunoregulation; improved; in vivo; keratinocyte; limb amputation; male; men; methicillin resistant Staphylococcus aureus; migration; mortality; negative affect; neutrophil; novel; novel strategies; psychosocial; receptor; receptor function; recruit; response; sex; sexual dimorphism; skin wound; therapy design; trafficking; treatment strategy; wound; wound closure; wound healing

#7 PROJECT SUMMARY Skin wound bacterial infections pose a significant health care burden in the US. They are frequently caused by Staphylococcus aureus and can be worsened by secondary complications like bacteremia. Of note, males have a 2-fold higher incidence of S. aureus infection than females in the US. While the higher susceptibility to S. aureus infection in males can also be observed in mice, reasons for this sex dimorphism are not well defined. What is known is that optimal host responses to wound infection need balanced pro- and anti- inflammatory signals by skin and resident immune cells. For example, neutrophil influx to help clear infections is facilitated by Toll-like receptor (TLR)-dependent pro-inflammatory cytokines and antimicrobial peptide (AMP) secretion by keratinocytes. Consequently, dysregulation or sex dimorphisms of any these host responses would negatively affect wound infection outcomes. In fact, our lab has established in the last several years that overactivation of the nicotinic acetylcholine receptor (nAChR) subtype CHRNA7 may play a prominent role in impairing the host defense against skin infection in mice and humans by lowering TLR2-mediated inflammation, AMP production, and neutrophil influx to the wound infection site. However, the relative contribution of keratinocyte CHRNA7 vs. immune cell CHRNA7 to this host response suppression is unknown. We have also not elucidated the CHRNA7-dependent downstream signaling mechanism(s) leading to the above phenotypes and not examined sex dimorphisms in CHRNA7 responses in the context of skin inflammation and wound infection. In this proposal, we will address two specific aims. 1) We will test our hypotheses that keratinocyte CHRNA7 is a major player in dampening wound antimicrobial responses and immune cell recruitment in a sex specific manner, which is supported by our pilot data. 2) We will elucidate the signaling mechanisms by which keratinocyte CHRNA7 impairs TLR2-mediated the production of immunomodulatory factors that are necessary for downstream neutrophil antimicrobial responses in vitro. Our studies will begin to unravel a fundamentally new mechanism by which keratinocyte CHRNA7 modulates wound antimicrobial responses in a sex specific manner and may be the basis for establishing CHRNA7 as a novel target for pharmacologic interventions that are designed to improve wound healing outcomes in both men and women.

#7项目总结 皮肤伤口细菌感染在美国造成了重大的医疗保健负担。它们通常由以下原因引起： 金黄色葡萄球菌，并可因继发性并发症如菌血症而恶化。值得注意的是，男性 有2倍高的感染率在美国，金黄色葡萄球菌感染率高于女性。而对高血压的易感性 S.在雄性小鼠中也可以观察到金黄色葡萄球菌感染，这种性别二态性的原因尚不清楚 定义了已知的是，对伤口感染的最佳宿主反应需要平衡的亲和抗- 炎症信号通过皮肤和常驻免疫细胞。例如，中性粒细胞流入有助于清除感染 由Toll样受体（TLR）依赖性促炎细胞因子和抗菌肽（AMP）促进 角质形成细胞分泌。因此，任何这些宿主反应的失调或性别二型 会对伤口感染产生负面影响。事实上，我们的实验室在过去的几年里已经确定， 烟碱乙酰胆碱受体（nAChR）亚型CHRNA7的过度激活可能在 通过降低TLR2介导的免疫应答， 炎症、AMP产生和中性粒细胞流入伤口感染部位。但是，相对 角质形成细胞CHRNA7相对于免疫细胞CHRNA7对这种宿主应答抑制的贡献是未知的。 我们也没有阐明导致CHRNA7依赖性下游信号传导机制。 上述表型，未检查皮肤中CHRNA7反应的性别二型性 炎症和伤口感染。在本建议中，我们将针对两个具体目标。1)我们将测试 假设角质形成细胞CHRNA7是抑制伤口抗菌反应的主要参与者， 免疫细胞以性别特异性方式募集，这得到了我们的试点数据的支持。2)我们将阐明 角质形成细胞CHRNA7通过其损害TLR2介导的 免疫调节因子是体外下游中性粒细胞抗微生物应答所必需的。我们 研究将开始揭示角质形成细胞CHRNA7调节的一种全新机制， 伤口抗菌反应以性别特异性的方式，并可能是建立CHRNA7作为一个基础， 药物干预的新目标，旨在改善伤口愈合的结果， 男人和女人