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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：
9131855
负责人：
SASHA H SHAFIKHANI
金额：
$ 15.5万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-18 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9131855
关键词：
Accounting Address Amputation Animal Model Animals Automobile Driving Bacteria Bacterial Infections Bioavailable Biochemical Biological Markers CCR1 gene Caring Cell Culture Techniques Chronic Comorbidity Complications of Diabetes Mellitus Data Diabetes Mellitus Diabetic Foot Ulcer Diabetic ulcer Diabetic wound Exhibits Foot Ulcer Healed Health Hospitalization Impaired wound healing Impairment Infection Infection Control Infiltration Inflammation Inflammatory Inflammatory Response Injury Interleukin-8B Receptor Invaded LTB4R gene Laboratories Lead Left Ligands Lower Extremity Mediating Modeling Molecular Molecular Target Morbidity - disease rate Nature Neutrophil Infiltration Non-Insulin-Dependent Diabetes Mellitus Normal tissue morphology Outcome Pain Patients Pattern recognition receptor Peptide Receptor Production Pseudomonas aeruginosa Quality of life Receptor Signaling Signal Transduction Source Specificity Staging Structure Therapeutic Time Tissues Toll-like receptors Type III Secretion System Pathway Ulcer Virulence Wound Healing antimicrobial antimicrobial peptide base chemokine combat conventional therapy cost diabetic fighting healing killings macrophage microbiome neutrophil novel strategies novel therapeutic intervention outcome forecast pathogen pathogenic bacteria response skills wound

项目摘要

DESCRIPTION (provided by applicant) 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 delayed neutrophil response in diabetic wounds after injury leads to impaired signaling through the pattern recognition receptors and reduced pathogen-specific antimicrobial peptides, potentiating the microbiome shift toward Pa, which drives diabetic wound toward the chronic non-healing outcome. 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.

描述（由申请人提供）足部溃疡是发达国家糖尿病患者住院的主要原因之一，也是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100万糖尿病患者在其生命的某个阶段发生足部溃疡，每年花费约250亿美元的护理费用，占美国所有下肢截肢的67%。长期以来，细菌感染一直被认为是糖尿病溃疡伤口愈合的主要障碍。微生物组向致病菌（如铜绿假单胞菌）的转变发生在糖尿病溃疡中，并与不良愈合预后相关。糖尿病伤口无法抵抗细菌感染的根本原因以及微生物组向致病菌转移的原因仍然知之甚少。基于我们的初步数据，我们的中心假设是损伤后糖尿病伤口中延迟的中性粒细胞反应导致通过模式识别受体的信号传导受损和病原体特异性抗微生物肽减少，从而增强微生物组向Pa转变，这将糖尿病伤口推向慢性不愈合结果。在本提案中，我们将：（目的1）确定糖尿病伤口中性粒细胞反应受损的分子机制：（目的2）评估延迟中性粒细胞反应对通过模式识别受体（PRRs）的信号传导的不利影响;和（目的3）评估延迟中性粒细胞应答对抗菌肽（AMP）产生的不利影响，特别是病原体特异性AMP，其使糖尿病伤口易于定植和微生物组向铜绿假单胞菌转移。我们还将评估促炎趋化因子和Toll样受体配体的治疗潜力，以恢复抗微生物防御，并通过在损伤后早期启动糖尿病伤口中的中性粒细胞反应来刺激愈合。