Syndecan-1 Regulations of Influenza Infection

Syndecan-1 流感感染调控

• 批准号: 8812061
• 负责人: PETER CHEN
• 金额: $ 41.07万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812061
• 关键词: Adult Respiratory Distress Syndrome; Antiviral Therapy; Apoptosis; Apoptotic; Appearance; Attenuated; Bacterial Infections; CD95 Antigens; Caspase Inhibitor; Cell membrane; Cell surface; Cessation of life; Communicable Diseases; Core Protein; Data; Dimethyl Sulfoxide; Disease; Disease Outbreaks; Epidemic; Epithelial; Event; Extracellular Domain; Immunity; Infection; Inflammatory; Influenza; Integration Host Factors; Lead; Lung; Lung Inflammation; Maps; Mediating; Mitochondria; Morbidity - disease rate; Mus; Pathway interactions; Patients; Proteoglycan; Proto-Oncogene Proteins c-akt; Receptor Signaling; Regulation; Respiratory Failure; Secondary to; Signal Transduction; TNFSF10 gene; Testing; Vaccine Production; Viral; Viral Drug Resistance; Viral Pneumonia; Virus Diseases; Wild Type Mouse; Work; airway epithelium; burden of illness; lung injury; mortality; mouse model; novel; novel therapeutics; pandemic disease; public health relevance; receptor; response; superinfection; syndecan

Project Summary/Abstract Influenza is a yearly epidemic that causes up to 500,000 global deaths annually. Most patients die of respiratory failure from either a primary viral pneumonia or a secondary bacterial infection. Therefore, finding host factors that can limit the progression of lung injury may lead to novel therapies for this deadly disease. Our preliminary data demonstrate that syndecan-1, a cell surface proteoglycan, regulates lung inflammation and reduces morbidity and mortality in mice after infection. Moreover, our data indicate that syndecan-1 restricts lung injury after influenza infection by limiting apoptosis in the airway epithelium. Our findings also show that syndecan-1 activates AKT, a pro-survival signal that can inhibit apoptosis. The central hypothesis for our proposal is that syndecan-1 is a pro-survival signal that attenuates epithelial apoptosis after influenza infection to limit lung injury. We will evaluate the mechanisms by which syndecan-1 regulates various apoptotic pathways. Additionally, we will investigate whether syndecan-1 suppresses apoptosis via activation of AKT. Finally, we will identify novel syndecan-1 co- receptors that mediate its cytoprotective effect. These studies will provide a platform for novel therapeutics that can target the airway epithelium to limit lung injury after influenza infection. This work may also have broader implications on other infectious diseases (viral and non-viral) of the lungs.

项目总结/摘要 流感是一种年度流行病，每年导致全球50万人死亡。大多数患者 死于原发性病毒性肺炎或继发性细菌感染引起的呼吸衰竭。 因此，找到能够限制肺损伤进展的宿主因素可能会导致新的肺损伤。 治疗这种致命疾病的方法我们的初步数据表明，syndecan-1，一种细胞， 表面蛋白聚糖，调节肺部炎症并降低小鼠的发病率和死亡率 感染后此外，我们的数据表明，syndecan-1限制流感后肺损伤 通过限制气道上皮细胞凋亡来抑制感染。我们的发现还表明syndecan-1 激活AKT，一种可以抑制细胞凋亡的促生存信号。我们的核心假设是 提出syndecan-1是一种促存活信号，在细胞凋亡后减弱上皮细胞凋亡。 流感感染以限制肺损伤。我们将评估syndecan-1 调节各种凋亡途径。此外，我们将研究syndecan-1是否 通过激活AKT抑制细胞凋亡。最后，我们将确定新的syndecan-1共- 受体介导其细胞保护作用。这些研究将提供一个平台， 可以靶向气道上皮以限制流感感染后肺损伤的治疗剂。 这项工作也可能对其他传染病（病毒和非病毒）产生更广泛的影响。 肺的。