Factors Leading to Enhanced Pseudomonas Aeruginosa Infection in Diabetic Wounds

导致糖尿病伤口铜绿假单胞菌感染增强的因素

基本信息

批准号：
9974298
负责人：
SASHA H SHAFIKHANI
金额：
$ 34.88万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-20 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974298
关键词：
Accounting Address Amputation Animal Model Animals Automobile Driving Bacterial Infections Bioavailable Biochemical Biological Markers CC chemokine receptor 1 Caring Cell Culture Techniques Chronic Complications of Diabetes Mellitus Data Diabetes Mellitus Diabetic Foot Ulcer Exhibits Foot Ulcer Goals Gram-Negative Bacteria Hospitalization Impaired healing Impairment Infection Infection Control Infiltration Inflammation Inflammatory Inflammatory Response Injury Insulin-Dependent Diabetes Mellitus Interleukin-8B Receptor Invaded LTB4R gene Laboratories Ligands Lower Extremity Mediating Modeling Molecular Molecular Target Morbidity - disease rate Neutrophil Infiltration Neutrophilia Non-Insulin-Dependent Diabetes Mellitus Normal tissue morphology Pain Pathogenicity Patients Pattern recognition receptor Peptide Receptor Production Pseudomonas aeruginosa Pseudomonas aeruginosa infection Publishing Quality of life Receptor Signaling Signal Transduction Source Specificity Structure Therapeutic Time Tissues Toll-like receptors Type III Secretion System Pathway Virulence Wound models antimicrobial antimicrobial peptide bacteriome base chemokine chronic ulcer combat commensal bacteria comorbidity conventional therapy cost diabetic diabetic ulcer fighting healing macrophage microbiome neutrophil novel strategies novel therapeutic intervention outcome forecast pathogen pathogenic bacteria prevent receptor response skills wound wound healing

项目摘要

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.

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、痛苦和生活质量差。 25.8 仅在美国就有 100 万糖尿病患者在一生中的某个时刻出现足部溃疡，造成约 25 美元的损失每年的护理费用达 10 亿美元，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。的转变针对病原菌（例如铜绿假单胞菌）的微生物组发生在糖尿病性溃疡和糖尿病性溃疡中与不良的愈合预后相关。糖尿病伤口无法抵抗的根本原因细菌感染以及微生物组向致病菌转变的原因仍知之甚少。根据我们的初步数据，我们的中心假设是，损伤后早期中性粒细胞浸润不足糖尿病伤口——由于中性粒细胞通过甲酰化肽受体 (FPR) 的趋化反应受损 -- 导致 TLR 信号传导减少、炎症反应减少以及病原体特异性 AMP 减少表达，使糖尿病伤口容易受到病原菌感染，从而进一步加剧糖尿病伤口，使其走向高炎症和慢性状态。在本提案中，我们将：（目标 1）确定糖尿病伤口中性粒细胞反应受损的分子机制；（目标 2）评估中性粒细胞反应延迟对模式识别受体 (PRR) 信号传导产生不利影响；和（目标 3）评估中性粒细胞反应延迟对抗菌肽 (AMP) 产生的不利影响，特别是病原体特异性 AMP，使糖尿病伤口容易受到定植和微生物群的影响转向铜绿假单胞菌。我们还将评估促炎剂的治疗潜力趋化因子和 Toll 样受体配体可恢复抗菌防御并通过快速启动刺激愈合损伤后早期糖尿病伤口中的中性粒细胞反应。