Syndecan-1 Regulations of Influenza Infection

描述（由申请人提供）：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-1，一种细胞表面蛋白聚糖，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通过限制气道上皮细胞的凋亡来限制流感感染后的肺损伤。我们的研究结果还表明，syndecan-1激活AKT，一种可以抑制细胞凋亡的促生存信号。我们项目的中心假设是syndecan-1是一种促生存信号，在流感感染后减弱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共受体介导的细胞保护作用。这些研究将为靶向气道上皮以限制流感感染后肺损伤的新疗法提供平台。这项工作也可能对其他肺部感染性疾病（病毒性和非病毒性）产生更广泛的影响。

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.