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: 8645699
• 负责人: Yang Jin
• 金额: $ 42.96万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645699
• 关键词: Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Animal Model; Apoptosis; Biology; Blood Vessels; Caveolae; Cell Death; Cell Death Signaling Process; Cell membrane; Cells; Cessation of life; Cholesterol; Data; Epithelial Cells; Extravasation; Fas Signaling Pathway; Functional disorder; Human; Hyperoxia; In Vitro; Integral Membrane Protein; Knockout Mice; Lead; Lung; Lung Inflammation; Mediating; Membrane Microdomains; Modeling; Modification; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Play; Prevention; Proteins; Publishing; Pulmonary Edema; Regulation; Research Personnel; Resistance; Role; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Sphingolipids; Stream; Syndrome; Testing; Therapeutic; Work; base; caveolin 1; cell injury; flotillin; in vivo; lung injury; mortality; novel; prevent; respiratory; survivin; therapeutic development

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）是造成严重发病率和死亡率的破坏性综合征。ARDS的发病机制仍不清楚，治疗选择仍然有限。高氧性肺损伤是一种模拟人类急性呼吸窘迫综合征（ARDS）的成熟模型，已被研究者广泛应用。肺上皮细胞死亡是急性肺损伤的一个重要特征，在急性肺损伤/急性呼吸窘迫综合征的发病机制中起着至关重要的作用。细胞死亡是由信号分子调控的，这些信号分子已被证明聚集在脂筏上。Caveolin-1 （cav-1）和flotillin1（flot1）已被鉴定为脂质筏标记蛋白，在多种肺细胞中高表达。然而，对浮体在呼吸生物学中的调控和功能研究甚少。根据我们已发表的和初步的研究，我们认为cav-1和flot1是在ALI和高氧诱导的上皮细胞死亡的发病机制中起关键作用的重要效应分子。我们发表的研究表明，cav-1缺失小鼠对高氧诱导的ALI具有抗性。自我们之前提交以来，我们新发表的数据进一步表明，cav-1通过抑制survivin增加高氧诱导的细胞凋亡。与cav-1相反，我们的数据显示flot1可以防止高氧诱导的细胞死亡。Cav-1和flot1通过独立于FasL的Fas途径共同调节高氧诱导的细胞死亡。高氧后，Flot1和cav-1均与Fas相互作用，表明cav-1与Flot1相互作用，介导死亡信号通路。我们假设cav-1、flot1及其串扰通过调节Fas信号通路调节高氧诱导的上皮细胞死亡和ALI。我们预计，我们的研究将导致对急性肺损伤治疗方法发展的新靶点的确定。我们将在以下具体目标中验证我们的假设：Aim1I：确定cav-1的功能作用以及cav-1介导高氧诱导上皮细胞死亡的潜在机制。目的2：探讨flot1在高氧诱导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flot1在高氧诱导肺上皮细胞死亡和肺损伤中的交互作用。