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）是一种严重的综合征，在重症监护病房中可导致严重的发病率和死亡率。尽管最近在保护性低潮气量治疗策略方面取得了进展，但对ARDS的发病机制仍知之甚少，治疗选择仍然有限。高氧诱导的肺损伤是一种成熟的模拟人类ARDS的模型，在过去的几十年中被研究者广泛用于更好地了解ARDS的发病机制。CCN家族是20世纪90年代报道的一类新的分子，具有多种生物学功能，包括创伤愈合、血管生成、纤维化、肿瘤发生和肺发育。CCN家族包括六种30-40 kDa的蛋白质，这些蛋白质极其富含半胱氨酸，并以其前三个成员（富含半胱氨酸61（Cyr 61）、结缔组织生长因子（CTGF）和肾母细胞瘤过表达（NOV））命名。Cyr 61是CCN蛋白之一，被鉴定为TGF-β 1诱导的立即早期基因，并被证明参与细胞增殖、粘附和对应激的早期反应。尽管越来越多的证据表明Cyr 61在其他组织器官的血管生成、伤口愈合和修复中至关重要，但Cyr 61尚未在肺细胞或肺部疾病的体内模型中进行广泛研究，特别是其在急性肺损伤中的潜在作用。我们的实验室专注于了解更多关于这个有趣的分子，可能是急性肺损伤的新分子靶点。为此，我们已经获得了挑衅性的初步数据，Cyr 61是高氧后在肺组织和各种肺细胞中高度表达。我们最近的初步数据还表明，Cyr 61在体外可防止高氧诱导的肺上皮细胞死亡。Cyr 61的这种细胞保护作用可能通过Akt途径发挥作用。基于我们的初步研究，我们假设Cyr 61的表达受高氧的转录调控，并通过Akt相关通路对高氧产生细胞保护作用。我们进一步假设Cyr 61在体内保护高氧诱导的急性肺损伤。我们将通过解决以下具体目标来检验我们的假设： 具体目的I：确定高氧后Cyr 61表达的调节 具体目的II：确定Cyr 61在体外保护免受高氧诱导的细胞死亡和损伤的机制 具体目的III：确定Cyr 61在体内保护免受高氧诱导的肺损伤的机制 (End摘要）

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)