Syndecan-1 Regulations of Influenza Infection

Syndecan-1 流感感染调控

• 批准号: 9198040
• 负责人: PETER CHEN
• 金额: $ 42.5万
• 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 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198040
• 关键词: Adult Respiratory Distress Syndrome; Alpha Cell; 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; Periodicity; 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; 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

DESCRIPTION (provided by applicant): 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 te airway epithelium. Our findings also show that syndecan-1 activates AKT, a pro-survival signal that can inhibit apoptosis. The central hypothesis for our project 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.

描述(申请人提供)：流感是一种每年导致全球多达50万人死亡的流行病。大多数患者死于呼吸衰竭，要么死于原发病毒性肺炎，要么死于继发性细菌感染。因此，寻找可以限制肺损伤进展的宿主因素可能会导致这种致命疾病的新疗法。我们的初步数据表明，Syndecan-1，一种细胞表面的蛋白多糖，调节肺部炎症，降低感染后小鼠的发病率和死亡率。此外，我们的数据表明Syndecan-1通过限制呼吸道上皮细胞的凋亡来抑制流感感染后的肺损伤。我们的发现还表明，Syndecan-1激活了AKT，这是一种能够抑制细胞凋亡的促生存信号。我们项目的中心假设是Syndecan-1是一种促进生存的信号，它可以减弱流感感染后的上皮细胞凋亡，以限制肺损伤。我们将评估Syndecan-1调节各种凋亡途径的机制。此外，我们还将研究Syndecan-1是否通过激活AKT来抑制细胞凋亡。最后，我们将确定新的Syndecan-1辅助受体来介导其细胞保护作用。这些研究将为以呼吸道上皮为靶点的新疗法提供一个平台，以限制流感感染后的肺损伤。这项工作也可能对肺部的其他传染病(病毒和非病毒)产生更广泛的影响。