Syndecan-1 Regulations of Influenza Infection

Syndecan-1 流感感染调控

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：流感是每年一次的流行病，每年最多可导致500,000例全球死亡。大多数患者因原发性肺炎或继发性细菌感染而死于呼吸道衰竭。因此，寻找可以限制肺部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（一种细胞表面蛋白聚糖）调节肺部炎症并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te气道上皮细胞凋亡而限制了流感感染后的肺损伤。我们的发现还表明，Syndecan-1激活AKT，这是一种可以抑制凋亡的临床信号。我们项目的中心假设是syndecan-1是一个亲卵巢的信号，在流感感染后减弱上皮凋亡以限制肺损伤，我们将评估Syndecan-1调节各种凋亡途径的机制。此外，我们将研究Syndecan-1是否通过激活AKT抑制凋亡。最后，我们将确定介导其细胞保护作用的新型Syndecan-1共受体。这些研究将为新型治疗剂提供一个平台，该平台可以针对气道上皮，以限制流感感染后的肺损伤。这项工作也可能对肺的其他传染病（病毒和非病毒）具有更广泛的影响。