Regulation and function of Cyr61 in hyperoxia induced acute lung injury

描述(由申请人提供)： 成人呼吸窘迫综合征(ARDS)是一种破坏性的综合征，在我们的重症监护病房中导致显著的发病率和死亡率。尽管保护性低潮气量呼吸策略最近取得了进展，但ARDS的发病机制仍然知之甚少，治疗选择仍然有限。高氧性肺损伤是一种成熟的模拟人类ARDS的模型，在过去的几十年里被研究人员广泛使用来更好地了解ARDS的发病机制。20世纪90年代S报道了一类新的分子，命名为CCN家族，具有多种生物学功能，包括伤口愈合、血管生成、纤维化形成、肿瘤发生和肺发育。CCN家族包括6个高度富含半胱氨酸的30-40 kDa蛋白质，并以其前三个成员(富含半胱氨酸的61(Cyr61)、结缔组织生长因子(CTGF)和肾母细胞瘤过度表达(NOV))命名。Cyr61是CCN蛋白之一，被鉴定为转化生长因子-n诱导的即刻早期基因，参与细胞增殖、黏附和应激的早期反应。尽管越来越多的证据表明，Cyr61在血管生成、伤口愈合和其他组织器官的修复中起关键作用，但在肺细胞或肺部疾病的体内模型中，特别是在急性肺损伤中的潜在作用，尚未得到广泛的研究。我们的实验室致力于更多地了解这种耐人寻味的分子，它可能是急性肺损伤的新分子靶点。为此，我们已经获得了具有挑衅性的初步数据，即Cyr61在高氧后的肺组织和各种肺细胞中高表达。我们最近的初步数据也表明，Cyr61在体外对高氧诱导的肺上皮细胞死亡具有保护作用。Cyr61的这种细胞保护作用可能通过Akt途径发挥作用。根据我们的初步研究，我们假设Cyr61的表达受到高氧的转录调控，并通过Akt相关途径提供对高氧的细胞保护。我们进一步假设Cyr61在体内对高氧诱导的急性肺损伤有保护作用。我们将通过解决以下具体目标来验证我们的假设： 特异性目标I：确定高氧后Cyr61表达的调节 特异靶II：体外研究Cyr61对高氧诱导的细胞死亡和损伤的保护作用机制(S) 特异性靶点III：确定Cyr61对高氧性肺损伤的保护作用机制(S) (摘要结束)

DESCRIPTION (provided by applicant): Adult respiratory distress syndrome (ARDS) is a devastating syndrome responsible for significant morbidity and mortality in our intensive care units. The pathogenesis of ARDS is still poorly understood and therapeutic options remain limited despite the recent progress in protective low tidal volume ventilatory strategies. Hyperoxia-induced lung injury is a well established model which mimics human ARDS and has been used extensively by investigators during the past several decades to better understand the pathogenesis of ARDS. A novel class of molecules named "CCN" family were reported in the 1990's, having diverse biological functions including wound healing, angiogenesis, fibrogenesis, tumorigenesis and lung development. The CCN family includes six 30-40 kDa proteins that are extremely cysteine-rich and was named after its first three members (cysteine-rich 61 (Cyr61), connective tissue growth factor (CTGF) and nephroblastoma overexpressed (NOV). Cyr61, one of the CCN proteins, was identified as a TGF-n inducible immediate early gene and demonstrated to be involved in cell proliferation, adhesion and early response to stress. Despite the accumulating evidence that Cyr61 is critical in angiogenesis, wound healing and repair in other tissue organs, Cyr61 has not been extensively studied in lung cells or in vivo models of lung diseases, especially its potential roles in acute lung injury. Our laboratory has focused in learning more about this intriguing molecule, potentially a novel molecular target in acute lung injury. To this end, we have obtained provocative preliminary data that Cyr61 is highly expressed in lung tissues and in various lung cells after hyperoxia. Our recent preliminary data also demonstrate that Cyr61 protects against hyperoxia-induced lung epithelial cell death in vitro. This cytoprotective effect of Cyr61 might function via Akt pathways. Based on our Preliminary Studies, we hypothesize that Cyr61 expression is regulated by hyperoxia transcriptionally and confers cytoprotection against hyperoxia via Akt related pathways. We further hypothesize that Cyr61 protects hyperoxia-induced acute lung injury in vivo. We will test our hypothesis by addressing the following specific aims: Specific Aims I: To determine the regulation of Cyr61 expression after hyperoxia Specific Aims II: To determine the mechanism(s) by which Cyr61 protects against hyperoxia-induced cell death and injury in vitro Specific Aims III: To determine the mechanism(s) by which Cyr61 protects against hyperoxia-induced lung injury in vivo (End of Abstract)