Cross talk between cav-1 and flot1 in lung injury

cav-1 和 flot1 在肺损伤中的串扰

• 批准号: 9181729
• 负责人: Yang Jin
• 金额: $ 27.72万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181729
• 关键词: Cross; talk; between; cav; flot1

DESCRIPTION (provided by applicant): Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are devastating syndromes responsible for significant morbidity and mortality. The pathogenesis of ARDS is still poorly understood and therapeutic options remain limited. Hyperoxia-induced lung injury is an established model which mimics human ARDS and has been used extensively by investigators. Lung epithelial cell death is a key feature of ALI and is crucial in the pathogenesis of ALI /ARDS. Cell death is regulated by signaling molecules, which have been shown to congregate on lipid rafts. Caveolin-1 (cav-1) and flotillin1(flot1) have been identified as lipid raft marker proteins, which are highly expressed in various lung cells. However, the regulation and function of flot1 in respiratory biology has been poorly, if at all, studied. Based on our published and preliminary studies, we believe that cav-1 and flot1 are important effector molecules which play critical roles in the pathogenesis of ALI and hyperoxia-induced epithelial cell death. Our published work has demonstrated that cav-1 null mice are resistant to hyperoxia induced ALI. Since our previous submission, our newly published data further showed that cav-1 increases hyperoxia-induced apoptosis via suppressing survivin. In contrast to cav-1, our data showed that flot1 protects against hyperoxia induced cell death. Cav-1 and flot1 together regulate hyperoxia induced cell death via Fas pathways independent of FasL. Flot1 and cav-1 both interacted with Fas after hyperoxia, indicating that cav-1 and flot1 cross talk and mediate the death signaling. We hypothesize that cav-1, flot1 and their cross-talk modulate hyperoxia induced epithelial cell death and ALI via regulating Fas signaling pathways. We anticipate that our studies will lead to the identification of novel targets for the development of therapeutic approaches against acute lung injury. We will test our hypothesis in the following specific aims: Aim1I: To determine the functional role of cav-1 and the underlying mechanisms by which cav-1 mediates hyperoxia induced epithelial cell death. Aim 2: To determine the regulation and function of flot1 in hyperoxia induced lung epithelial cell death and lung injury. Aim 3: To determine the cross-talk between cav-1 and flot1 in hyperoxia induced lung epithelial cell death and lung injury.

描述（由申请人提供）：急性肺损伤（ALI）及其严重形式的急性呼吸窘迫综合征（ARDS）是导致显著发病率和死亡率的破坏性综合征。ARDS的发病机制仍然知之甚少，治疗选择仍然有限。高氧诱导的肺损伤是一种模拟人类ARDS的成熟模型，已被研究者广泛使用。肺上皮细胞死亡是ALI的一个重要特征，在ALI /ARDS的发病机制中起重要作用。细胞死亡是由信号分子调节的，这些信号分子聚集在脂筏上。Caveolin-1（cav-1）和Flotillin 1（flot 1）是脂筏标记蛋白，在多种肺细胞中高表达。然而，flot 1在呼吸生物学中的调节和功能研究很少，如果有的话。基于我们已发表的和初步的研究，我们认为cav-1和flot 1是重要的效应分子，在ALI和高氧诱导的上皮细胞死亡的发病机制中起关键作用。我们已发表的工作已经证明cav-1基因敲除小鼠对高氧诱导的ALI具有抗性。自我们之前的报告以来，我们新发表的数据进一步表明cav-1通过抑制生存素增加高氧诱导的细胞凋亡。与cav-1相反，我们的数据表明flot 1可以防止高氧诱导的细胞死亡。Cav-1和flot 1共同调控高氧诱导的细胞死亡，其调控途径不依赖于FasL。高氧后Flot 1和cav-1均与Fas相互作用，表明cav-1和flot 1相互作用并介导死亡信号。我们推测cav-1、flot 1及其相互作用可能通过调节Fas信号通路来调节高氧诱导的上皮细胞死亡和ALI。我们预计，我们的研究将导致识别新的目标，为发展的治疗方法，对急性肺损伤。我们将测试我们的假设在以下具体目标：目的1 I：确定cav-1的功能作用和cav-1介导高氧诱导的上皮细胞死亡的潜在机制。目的2：探讨flot 1在高氧致肺上皮细胞死亡和肺损伤中的调控作用。目的3：探讨cav-1和flot 1在高氧诱导的肺上皮细胞死亡和肺损伤中的相互作用。

项目成果

Caveolin-1 mediates Fas-BID signaling in hyperoxia-induced apoptosis.

• DOI: 10.1016/j.freeradbiomed.2011.02.031
• 发表时间: 2011-05-15
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Zhang, Meng;Lee, Seon-Jin;An, ChangHyeok;Xu, Jin-fu;Joshi, Bharat;Nabi, Ivan R.;Choi, Augustine M. K.;Jin, Yang
• 通讯作者: Jin, Yang

Cross talk between autophagy and apoptosis in pulmonary hypertension.

• DOI: 10.4103/2045-8932.105029
• 发表时间: 2012-10
• 期刊: Pulmonary circulation
• 影响因子: 2.6
• 作者: Jin Y;Choi AM
• 通讯作者: Choi AM

Flotillin-2 modulates fas signaling mediated apoptosis after hyperoxia in lung epithelial cells.

• DOI: 10.1371/journal.pone.0077519
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wei S;Moon HG;Zheng Y;Liang X;An CH;Jin Y
• 通讯作者: Jin Y

CCN1 secretion induced by cigarette smoking extracts augments IL-8 release from bronchial epithelial cells.

• DOI: 10.1371/journal.pone.0068199
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Moon HG;Zheng Y;An CH;Kim YK;Jin Y
• 通讯作者: Jin Y

Suppression of PTRF alleviates the polymicrobial sepsis induced by cecal ligation and puncture in mice.

抑制 PTRF 可减轻小鼠盲肠结扎和穿刺引起的多种微生物败血症。

• DOI: 10.1093/infdis/jit364
• 发表时间: 2013
• 期刊: The Journal of infectious diseases
• 作者: Zheng,Yijie;Lee,Seonjin;Liang,Xiaoliang;Wei,Shuquan;Moon,Hyung-Geun;Jin,Yang
• 通讯作者: Jin,Yang