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: 8686894
• 负责人: SHANJANA AWASTHI
• 金额: $ 24.73万
• 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/8686894
• 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.

肺部感染是世界范围内发病率和死亡率的主要原因。严重的肺部感染会导致呼吸窘迫综合征，目前尚无特效治疗方法。随着由多药耐药病原体引起的肺部感染的增加以及控制相关炎症的“神奇药物”的不可用，开发新的治疗方法很重要。理想的治疗方法是能够抑制炎症反应，但保持抗病原体宿主防御和肺内稳态。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疗法。表面活性剂蛋白（SP）-A和Toll样受体（TLR）分别被称为“分泌型”和“信号传导型”病原体识别受体。SP-A和TLR 4之间的相互作用抑制TNF-α反应，但保留抗原呈递细胞的吞噬活性。因此，SP-A的TLR 4相互作用区域，模仿SP-A的这些特性，可以开发成一种新的SP-A为基础的免疫。利用尖端技术，我们最近鉴定了SP-A的TLR 4相互作用区域（SPA 4肽）。本申请的目的是确定SPA 4肽的生物学相关性并确定其作用机制。我们假设SPA 4肽将抑制TLR 4诱导的炎症，同时维持TLR 4介导的细菌吞噬和清除。具体目标是：（1）确定SPA 4肽是否在肺部炎症的动物模型中抑制炎症反应并改善临床症状，（2）确定SPA 4肽是否在细胞水平上抑制炎症反应并维持吞噬反应，和（3）评估SPA 4肽在肺部感染和炎症的临床相关动物模型中的生物学作用。这个项目是创新的，因为它使用了一个独特的概念，即开发一种免疫系统，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。预计基于SP-A的治疗剂将对改善感染和炎症期间的肺部健康产生重大影响。