Control of Lung Inflammation by a TLR4-interacting SPA-derived Peptide

通过 TLR4 相互作用的 SPA 衍生肽控制肺部炎症

• 批准号: 8465565
• 负责人: SHANJANA AWASTHI
• 金额: $ 25.16万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8465565
• 关键词: Acute; Admission activity; Adult Respiratory Distress Syndrome; Alveolar; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Binding; Biodistribution; Biological; Bystander Effect; C-terminal; Cells; Chemical Surfactants; Clinical; Communicable Diseases; Curosurf; Data; Dendritic Cells; Development; Epithelial Cells; Escherichia coli; Goals; Health; Homeostasis; Host Defense; Host Defense Mechanism; Immune; Immune system; Immunomodulators; Immunotherapeutic agent; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Intensive Care Units; Lead; Left; Life; Lipids; Lipopolysaccharides; Lung; Lung Inflammation; Lung diseases; Maintenance; Measures; Mechanical ventilation; Mediating; Modeling; Monitor; Morbidity - disease rate; Multi-Drug Resistance; Mus; N-terminal; Nitrates; Nitrites; Oklahoma; Patients; Peptides; Phagocytosis; Pharmaceutical Preparations; Pharmacotherapy; Play; Pre-Clinical Model; Property; Proteins; Pseudomonas aeruginosa; Public Health; Pulmonary Surfactant-Associated Protein A; Pulmonary alveolar structure; Reaction; Respiratory Mechanics; Respiratory physiology; Role; Signal Transduction; Signaling Molecule; Stimulus; Symptoms; TLR4 gene; TNF gene; Technology; Therapeutic; Toll-like receptors; base; calreticulin; clinically relevant; cytokine; improved; in vivo Model; inhibitor/antagonist; innovation; lung injury; macrophage; mortality; novel; novel therapeutics; pathogen; receptor; respiratory distress syndrome; response; screening; surfactant; therapy development; uptake

Lung infections are a major cause of morbidity and mortality worldwide. Serious lung infections lead to respiratory distress syndrome for which there is no specific treatment available. In the wake of rise in lung infections caused by multi-drug resistant pathogens and unavailability of a "wonder-drug" to control associated inflammation, it is important to develop novel therapies. An ideal therapeutic would be the one that can suppress the inflammatory response but preserve the anti-pathogen host defense and lung homeostasis. Our long term goal is to develop therapies based on boosting the natural host defense mechanisms mediated by pathogen-recognition receptors. Surfactant protein (SP)-A and Toll-like receptor (TLR) are known as "secretory" and "signaling" pathogen-recognition receptors, respectively. Interaction between SP-A and TLR4 inhibits the TNF-a response but preserves the phagocytic activity of antigen-presenting cells. Thus, a TLR4-interacting region of SP-A, mimicking these properties of SP-A may be developed into a novel SP-A-based immunotherapeutic. Using cutting-edge technology, we have recently identified a TLR4-interacfing region of SP-A (SPA4 peptide). The objective of this application is to define the biological relevance and determine the mechanism of action of SPA4 peptide. We hypothesize that the SPA4 peptide will inhibit TLR4-induced inflammation, while maintaining TLR4-mediated bacterial-phagocytosis and clearance. The specific aims are to: (1) determine if SPA4 peptide inhibits inflammatory responses and improves clinical symptoms in an animal model of lung inflammation, (2) determine if SPA4 peptide inhibits the inflammatory response and maintains the phagocytic response at a cellular level, and (3) assess the biological effects of SPA4 peptide in clinically-relevant animal models of lung infection and inflammation. This project is innovative because it uses a unique concept of developing an immunotherapeutic that will not only control inflammation, but also help maintain anti-pathogen responses and lung homeostasis. It is expected that an SP-A-based therapeutic will have a significant impact on improving lung health during infection and inflammation.

肺部感染是全世界发病率和死亡率的主要原因。严重的肺部感染导致呼吸窘迫综合征，目前还没有专门的治疗方法。随着多重耐药病原体引起的肺部感染的增加，以及无法获得控制相关炎症的“特效药”，开发新的治疗方法是重要的。理想的治疗方法是既能抑制炎症反应，又能保护抗病原体、宿主防御和肺内环境的稳定。我们的长期目标是开发基于增强病原体识别受体介导的自然宿主防御机制的治疗方法。表面活性蛋白(SP)-A和Toll样受体(TLR)分别被称为“分泌型”和“信号型”病原体识别受体。SP-A和TLR4的相互作用抑制了肿瘤坏死因子-α的反应，但保留了抗原提呈细胞的吞噬活性。因此，模拟SP-A的这些特性的SP-A的TLR4相互作用区可能被开发成一种基于SP-A的新型免疫治疗药物。利用尖端技术，我们最近发现了SP-A(SPA4肽)的TLR4结合区域。本应用的目的是确定SPA4多肽的生物学相关性并确定其作用机制。我们假设SPA4肽将抑制TLR4诱导的炎症，同时维持TLR4介导的细菌吞噬和清除。其具体目的是：(1)在肺部炎症动物模型中确定SPA4肽是否抑制炎症反应并改善临床症状；(2)确定SPA4肽是否在细胞水平上抑制炎症反应并维持吞噬反应；(3)在临床相关的肺部感染和炎症动物模型中评价SPA4肽的生物学效应。这个项目具有创新性，因为它使用了一个独特的概念，即开发一种免疫疗法，不仅可以控制炎症，还可以帮助维持抗病原体反应和肺内稳态。预计以SP-A为基础的治疗将对改善感染和炎症期间的肺健康产生重大影响。