Factors Leading to Enhanced Pseudomonas Aeruginosa Infection in Diabetic Wounds

足部溃疡是发达国家糖尿病患者住院的主要原因之一， 与糖尿病相关的主要发病率，导致患者疼痛、痛苦和生活质量下降。25.8 仅在美国，就有数百万糖尿病患者在一生中的某个时候患上足部溃疡，造成约25 每年花费10亿美元护理，占美国所有下肢截肢手术的67%。细菌 长期以来，感染一直被认为是糖尿病溃疡伤口愈合的主要障碍。世界经济形势的转变 对病原菌的微生物群，如铜绿假单胞菌，存在于糖尿病溃疡和 与不良的愈合预后有关。糖尿病创面无法抵抗的深层原因 细菌感染和微生物群向致病细菌转移的原因仍然知之甚少。 根据我们的初步数据，我们的中心假设是创伤后早期中性粒细胞浸润不足。 糖尿病创面--中性粒细胞通过甲酰化肽受体(FPR)的趋化反应受损 --导致TLR信号减少，炎症反应减少，病原体特异性AMP减少 表达，使糖尿病伤口容易受到致病菌的感染，从而进一步加剧 糖尿病伤口，将其推向高炎症和慢性状态。在这项提案中，我们将：(目标1)确定 糖尿病创面中性粒细胞反应受损的分子机制；(目的2)评估 中性粒细胞延迟反应对通过模式识别受体(PRRs)传递信号的不利影响；以及 (目的3)评估延迟的中性粒细胞反应对抗菌肽(AMPs)产生的不利影响， 尤其是病原体特异性的AMP，使糖尿病伤口容易被定植和微生物群侵袭 转向铜绿假单胞菌。我们还将评估促炎症药物的治疗潜力。 趋化因子和Toll样受体配体通过启动恢复抗菌防御和刺激愈合 糖尿病创面伤后早期的中性粒细胞反应。

Foot ulcers are one of the leading causes of hospitalization for people with diabetes in the developed world and a major morbidity associated with diabetes leading to pain, suffering, and a poor quality of life for patients. 25.8 million patients with diabetes in US alone develop foot ulcers at some point in their lives, costing approximately 25 billion dollars in care annually and accounting for 67% of all lower extremity amputations in the US. Bacterial infection has been long recognized as a major impediment to wound healing in diabetic ulcers. A shift in the microbiome toward pathogenic bacteria, such as Pseudomonas aeruginosa occurs in diabetic ulcers and correlates with a poor healing prognosis. The underlying reasons for the inability of diabetic wounds to fight off bacterial infection and the reasons for the microbiome shift toward pathogenic bacteria remain poorly understood. Based on our preliminary data, our central hypothesis is that inadequate neutrophil infiltration early after injury in diabetic wound-- due to impaired neutrophil chemotactic response through the formylated peptide receptor (FPR) -- leads to reduced TLR signaling, reduced inflammatory responses, and reduced pathogen-specific AMP expression, rendering diabetic wound vulnerable to infection with pathogenic bacteria, which further exacerbate diabetic wound, driving it toward hyper-inflammatory and chronic state. In this proposal, we will: (Aim 1) determine the molecular mechanisms that underlie the impaired neutrophil response in diabetic wound; (Aim 2) assess the adverse impact of delayed neutrophil response on signaling through pattern recognition receptors (PRRs); and (Aim 3) assess the adverse impact of delayed neutrophil response on antimicrobial peptides (AMPs) productions, particularly the pathogen-specific AMPs that render diabetic wounds vulnerable to colonization and microbiome shift toward Pseudomonas aeruginosa. We will also evaluate the therapeutic potential of pro-inflammatory chemokines and Toll-like receptor ligands to restore antimicrobial defenses and stimulate healing by jumpstarting the neutrophil response in diabetic wounds early after injury.