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

基本信息

批准号：
9100814
负责人：
SHANJANA AWASTHI
金额：
$ 23.89万
依托单位：
OKLAHOMA STATE UNIVERSITY STILLWATER
依托单位国家：
美国
项目类别：
财政年份：
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/9100814
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 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 multi-drug resistant pathogen novel novel therapeutics pathogen receptor respiratory distress syndrome response screening surfactant therapy development uptake

项目摘要

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和死亡的主要原因。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。随着多重耐药病原体引起的肺部感染增加，并且无法找到控制相关炎症的“特效药”，开发新疗法非常重要。一种理想的治疗方法是既能抑制炎症反应，又能保持抗病原体宿主防御和肺稳态的治疗方法。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。表面活性蛋白 (SP)-A 和 Toll 样受体 (TLR) 分别被称为“分泌”和“信号”病原体识别受体。 SP-A 和 TLR4 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，模仿 SP-A 的这些特性的 SP-A 的 TLR4 相互作用区域可能会被开发成一种新型的基于 SP-A 的免疫治疗药物。利用尖端技术，我们最近鉴定了 SP-A（SPA4 肽）的 TLR4 相互作用区域。本申请的目的是定义 SPA4 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。具体目标是：(1) 确定 SPA4 肽是否在肺部炎症动物模型中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，以及(3)评估SPA4肽在临床相关肺部感染和炎症动物模型中的生物学效应。该项目具有创新性，因为它采用了开发免疫治疗的独特概念，不仅可以控制炎症，还可以帮助维持抗病原体反应和肺稳态。预计基于 SP-A 的治疗将对改善感染和炎症期间的肺部健康产生重大影响。