Retrocyclin reinforcement of pulmonary defenses against viral aerosols

逆环素增强肺部针对病毒气溶胶的防御能力

• 批准号: 7229818
• 负责人: ROBERT IRVING LEHRER
• 金额: $ 11.21万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229818
• 关键词: Abattoirs; Aerosols; Air; Air Sacs; Alphavirus; Anti-Bacterial Agents; Antifungal Agents; Antiviral Agents; Arenaviridae; Baculoviruses; Behavior; Binding; Biological Assay; Biological Models; Bioterrorism; Bos taurus; Breathing; C-Type Lectins; Carbohydrates; Cattle; Cell fusion; Cells; Cercopithecidae; Collagen; Collectins; Coronaviridae; Defensins; Drug Formulations; Epithelial; Epithelial Cells; Exposure to; Family; Family suidae; Film; Flaviviridae; Genes; Glycoproteins; Gorilla gorilla; HIV-1; Head; Health; Herpes Simplex Infections; Human; In Vitro; Influenza; Language; Lectin; Leukocytes; Lipids; Liquid substance; Lung; Mannose Binding Lectin; Membrane; Mission; Mutation; Nonsense Codon; Orthomyxoviridae; Pan Genus; Pan troglodytes; Paramyxoviridae; Paramyxovirus; Peptide Signal Sequences; Peptide Synthesis; Peptides; Phase; Phospholipids; Plasma; Pongidae; Poxviridae; Property; Proteins; Pseudogenes; Psychological reinforcement; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactants; Pulmonary alveolar structure; Research Design; Serum; Serum Proteins; Severe Acute Respiratory Syndrome; Solid; Standards of Weights and Measures; Structure; Surface; Surface Plasmon Resonance; System; Tacaribe virus; Testing; Togaviridae; Vaccinia; Vesicle; Viral; Virus; Virus Diseases; West Nile virus; Yellow fever virus; alpha-Fetoproteins; analog; base; clinically significant; crosslink; cytotoxicity; fetal; milligram; monolayer; nonhuman primate; particle; prototype; response; retrocyclin; surfactant

DESCRIPTION (provided by applicant): Introduction: In addition to the a and ¿ defensins produced by human leukocytes and epithelial cells, many nonhuman primates produce ?-defensins, representing a third defensin subfamily. ?-defensins lack potent antibacterial or antifungal activity, but have broad antiviral properties. Retrocyclins are ?-defensins whose structures are based on the sequences of expressed (but untranslated) human ?-defensin pseudogenes. Broad, Long term objectives: To use retrocyclins to enhance pulmonary defenses to viral aerosols. Specific aims. 1. To test retrocyclins against potential viral bioterrorism agents, including Influenza A and B (Orthomyxoviridae), HPIV3 (Paramyxoviridae), West Nile and Yellow Fever virus (Flaviviridae) SARS-CoV (Coronaviridae), Vaccinia (Poxviridae), VEE, an alphavirus (Togaviridae), and Tacaribe virus (Arenaviridae) 2. To examine the interactions of retrocyclins with surfactant proteins SP-A and SP-D. 3. To test the effects actions of RC2 on monolayers and bilayers of pulmonary surfactant phospholipids. Research Design. Retrocyclin-2 (RC-2) and selected analogs will be prepared by solid phase peptide synthesis. Viruses will be tested in vitro by standard plaque reduction and CPE reduction assays. The effects of retrocyclins on the integrity of surfactant phospholipid films will be tested in monolayer systems by using a Langmuir-Blodgett trough, and in bilayer systems by using vesicles composed of surfactant lipids and associated surfactant proteins SP-B and SP-C. Binding of retrocyclins to SP-A and SP-D will be studied by surface plasmon resonance. Effects of retrocyclins on the intrinsic antiviral activity of SP-A and SP-D (and vice versa) will be studied using proteins purified from abattoir-obtained porcine lungs in standard plaque reduction and CPE reduction assays. Health relatedness and Agency Mission. This application is in direct response to PA 04-119. Lay language summary. Many natural viral infections begin with exposure to air that contains viruses. Viral aerosols may also allow bioterrorists to deliver incapacitating viruses. We propose to test the activity of retrocyclins (newly discovered antiviral peptides) against potential viral bioterrorism agents, and to determine their biocompatability with ELF-the thin fluid layer that covers the surface of the pulmonary air sacs.

描述（由申请人提供）： 简介：除了 a 和 ¿防御素由人类白细胞和上皮细胞产生，许多非人类灵长类动物产生β-防御素，代表第三种防御素亚家族，缺乏有效的抗菌或抗真菌活性，但具有广泛的抗病毒特性。表达（但未翻译）的人类 β-防御素假基因序列 广泛的长期目标：使用逆转录素来增强。具体目标 1. 测试逆环素对潜在的病毒生物恐怖因子，包括甲型和乙型流感病毒（正粘病毒科）、HPIV3（副粘病毒科）、西尼罗河病毒和黄热病病毒（黄病毒科）、SARS-CoV（冠状病毒科）。痘苗病毒（痘病毒科）、VEE、甲病毒（披膜病毒科）和Tacaribe 病毒（沙粒病毒科） 2. 检测逆环素与表面活性剂蛋白 SP-A 和 SP-D 的相互作用 3. 测试 RC2 对肺表面活性剂磷脂单层和双层的影响作用（RC）。 -2)并通过固相肽合成来制备病毒，并通过标准空斑减少和CPE减少测定来测试病毒的效果。逆环素对表面活性剂磷脂膜完整性的影响将通过使用 Langmuir-Blodgett 槽在单层系统中进行测试，并在双层系统中通过使用由表面活性剂脂质和相关表面活性剂蛋白 SP-B 和 SP-C 组成的囊泡进行测试。 -A 和 SP-D 将通过表面等离振子共振来研究逆转录环素对 SP-A 和 SP-D 内在抗病毒活性的影响。 SP-D（反之亦然）将使用从屠宰场获得的猪肺中纯化的蛋白质进行标准斑块减少和 CPE 减少测定，该应用是对 PA 04-119 的直接回应。许多自然病毒感染都是从暴露于含有病毒的空气中开始的，生物恐怖分子也可能会传播使病毒丧失能力的病毒（新发现的）。抗病毒肽）对抗潜在的病毒生物恐怖剂，并确定其与 ELF（覆盖肺气囊表面的薄液体层）的生物相容性。