Universal Anti-PAMP Agent to Improve Wound Healing

促进伤口愈合的通用抗 PAMP 剂

• 批准号: 10647897
• 负责人: Charles V Rice
• 金额: $ 7.39万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-16 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647897
• 关键词: Acetylmuramyl-Alanyl-Isoglutamine; Affinity; Anti-Inflammatory Agents; Antibiotic Resistance; Bacteremia; Bacteria; Binding; Binding Proteins; Binding Sites; Biochemical; CD14 gene; Calorimetry; Cells; Cessation of life; Chemicals; Complex; Dangerousness; Data; Development; Discrimination; Electrostatics; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Evaluation; Extracellular Matrix; Fibroblasts; Foundations; Government; Gram-Negative Bacteria; Gram-Positive Bacteria; Granulation Tissue; Health; Human; Immune; Immune response; Impaired wound healing; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Klebsiella pneumoniae; Knowledge; Libraries; Link; Lipopolysaccharides; Macrophage; Measures; Metalloproteases; Microbe; Microbial Biofilms; Mission; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Myelogenous; Natural Immunity; Nature; Nucleotides; Outcome Study; Pattern; Pattern Recognition; Pattern recognition receptor; Peptides; Peptidoglycan; Persons; Pharmaceutical Preparations; Phase; Play; Proteins; Proteolysis; Pseudomonas aeruginosa; Receptor Activation; Research; Rice; Risk Reduction; Role; Safety; Sepsis; Signal Transduction; Skin Tissue; Soft Tissue Infections; Specificity; Speed; Staphylococcus aureus; Structure-Activity Relationship; Technology; Testing; Therapeutic; Therapeutic Agents; Thinking; Tissues; Titrations; Toll-like receptors; Topical agent; Toxic effect; United States National Institutes of Health; Vertebral column; Virulence; Virulence Factors; Work; Wound Infection; Wound models; acute wound; chronic wound; combat; community setting; cytokine; disability; healing; health care settings; improved; in vivo; innovation; keratinocyte; lipopolysaccharide-binding protein; lipoteichoic acid; migration; mortality; necrotic tissue; novel; novel strategies; pathogen; pathogenic bacteria; peptidomimetics; phosphodiester; prevent; receptor; recurrent infection; resistance mechanism; response; transcription factor; wound; wound healing; Acetylmuramyl-Alanyl-Isoglutamine; Affinity; Anti-Inflammatory Agents; Antibiotic Resistance; Bacteremia; Bacteria; Binding; Binding Proteins; Binding Sites; Biochemical; CD14 gene; Calorimetry; Cells; Cessation of life; Chemicals; Complex; Dangerousness; Data; Development; Discrimination; Electrostatics; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Evaluation; Extracellular Matrix; Fibroblasts; Foundations; Government; Gram-Negative Bacteria; Gram-Positive Bacteria; Granulation Tissue; Health; Human; Immune; Immune response; Impaired wound healing; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Klebsiella pneumoniae; Knowledge; Libraries; Link; Lipopolysaccharides; Macrophage; Measures; Metalloproteases; Microbe; Microbial Biofilms; Mission; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Myelogenous; Natural Immunity; Nature; Nucleotides; Outcome Study; Pattern; Pattern Recognition; Pattern recognition receptor; Peptides; Peptidoglycan; Persons; Pharmaceutical Preparations; Phase; Play; Proteins; Proteolysis; Pseudomonas aeruginosa; Receptor Activation; Research; Rice; Risk Reduction; Role; Safety; Sepsis; Signal Transduction; Skin Tissue; Soft Tissue Infections; Specificity; Speed; Staphylococcus aureus; Structure-Activity Relationship; Technology; Testing; Therapeutic; Therapeutic Agents; Thinking; Tissues; Titrations; Toll-like receptors; Topical agent; Toxic effect; United States National Institutes of Health; Vertebral column; Virulence; Virulence Factors; Work; Wound Infection; Wound models; acute wound; chronic wound; combat; community setting; cytokine; disability; healing; health care settings; improved; in vivo; innovation; keratinocyte; lipopolysaccharide-binding protein; lipoteichoic acid; migration; mortality; necrotic tissue; novel; novel strategies; pathogen; pathogenic bacteria; peptidomimetics; phosphodiester; prevent; receptor; recurrent infection; resistance mechanism; response; transcription factor; wound; wound healing

Innate immunity has considerable specificity and can discriminate between individual species of microbes. In this regard, pathogens are “seen” as dangerous to the host and elicit an inflammatory response capable of destroying the microbes. This immune discrimination is achieved through the recognition of microbe- specific molecules (e.g., lipopolysaccharide, lipoteichoic acid, and peptidoglycan) by toll-like receptors on host cells. Lipopolysaccharide, lipoteichoic acid, and peptidoglycan arising from dangerous bacteria are known as Pathogen-Associated Molecular Pattern (PAMP) molecules. PAMPs impede wound healing by lengthening the inflammatory phase of healing and contributing to the development of chronic wounds. Preventing PAMPs from triggering the release of inflammatory cytokines will restore the optimal inflammatory response. However, successful drugs are elusive because PAMPs originate from many different species of Gram-negative and Gram- positive bacteria. Therefore, the need exists for a universal broad-spectrum therapeutic against LPS, LTA, and PGN bacterial PAMPs. The objective of this project is to investigate PEG-BPEI structure-activity relationships. The central hypothesis is that increasing the steric bulk of PEG-BPEI reduces its ability to bind with PAMPs from S. aureus, P. aeruginosa, E. coli, and K. pneumoniae and thus is unable to interfere with PAMP recognition by PRRs. We will test our central hypothesis with the following specific aims: Aim 1: Correlate PEG-BPEI steric effects with PAMP binding; Aim 2: Discover how PAMP + PEG-BPEI combinations reduce PRR activation. Data arising from these aims will be significant because they are expected to provide strong scientific justification for the continued development of anti-inflammatory agents applied to acute and chronic wounds. This project has added significance because the data will be used to evaluate the strategy of using this agent to bind bacterial PAMPs and prevent cytokine release; a strategy that enables other subsequent research and thinking. The proposed work is innovative because we fill the technological gap with multi-purpose agents that disable PAMPs, dissolve biofilms, and overcome antibiotic resistance mechanisms, making them superior to existing technology. The rationale is that the agent will improve wound healing by counteracting LPS, LTA, and PGN bacterial products that cause inflammation. Determining the ability to inhibit inflammatory cytokine release is necessary to evaluate the therapeutic opportunities of the chemical molecules. We envision our discoveries as topical agents applied to acute and chronic wounds because, in addition to the active moiety of the agent preventing cytokine release, it also disables antibiotic resistance mechanisms and disrupts the biofilm matrix. This versatility of this agent suggests that it may be an ideal therapeutic agent for use in the hundreds of millions of non-chronic skin or soft- tissue infections (SSTIs), and the 4.5 million chronic wound infections, that occur each year.

先天免疫已考虑特异性，可以区分 微生物。在这方面，病原体“认为”对宿主有危险并引起炎症反应 能够破坏微生物。这种免疫歧视是通过识别微生物来实现的 特定的分子（例如，通过宿主的Toll样受体在宿主的受体上 细胞。脂多糖，脂肪酸酸和辣椒糖来自危险细菌引起的 病原体相关的分子模式（PAMP）分子。弹药通过加长来阻碍伤口愈合 愈合的炎症阶段，并为慢性逻辑奖金的发展做出贡献。防止弹奏 触发炎症细胞因子的释放将恢复最佳炎症反应。然而， 成功的药物是弹性的，因为PAMP源自许多不同种类的革兰氏阴性和革兰氏阴性 阳性细菌。因此，存在针对LP，LTA和 PGN细菌疫苗。 该项目的目的是研究PEG-BPEI结构活性关系。中央 假设是，增加peg-bpei的空间大部分会降低其与金黄色葡萄球菌的毒池结合的能力， P.铜绿假单胞菌，大肠杆菌和肺炎。因此无法干扰PRRS的PAMP识别。我们 将通过以下特定目的检验我们的中心假设 PAMP结合；目标2：发现PAMP + PEG-BPEI组合如何减少PRR激活。来自 这些目标将是重要的，因为他们应该为持续 用于急性和慢性伤口的抗炎药的发展。这个项目添加了 意义是因为数据将用于评估使用该试剂结合细菌症状的策略 并防止细胞因子释放；一种策略，可以使其他随后的研究和思维。提议 工作具有创新性，因为我们用多用途的代理填补了技术空白 生物膜和克服抗生素耐药机制，使其优于现有技术。 理由是，代理将通过抵消LP，LTA和PGN细菌产品来改善伤口愈合 这会引起炎症。确定抑制炎性细胞因子释放的能力是为了评估 化学分子的治疗机会。我们设想我们的发现是应用的主题代理 急性和慢性伤口，因为除了防止细胞因子释放的药物的活性部分外， 它还禁用抗生素耐药机制并破坏生物膜基质。这个代理的这种多功能性 这表明它可能是用于数亿非少生皮肤或柔软的理想治疗剂 每年发生的组织感染（SSTI）和450万个慢性伤口感染。