Ventilator-induced diaphragmatic atrophy: role of FoxO signaling

呼吸机引起的膈肌萎缩：FoxO 信号传导的作用

• 批准号: 8426521
• 负责人: Scott K. Powers
• 金额: $ 20.14万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426521
• 关键词: Acute respiratory failure; Alveolar; Animals; Atrophic; Autophagocytosis; Biological; Cells; Clinical; Depressed mood; Development; Dominant-Negative Mutation; Down-Regulation; Environmental air flow; Event; Family; Fiber; Foundations; Functional disorder; Gene Delivery; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Intervention; Lead; Life; Mechanical ventilation; Mental Depression; Methods; Modeling; Muscle; Muscle Weakness; Pathway interactions; Patients; Play; Prevention; Prevention strategy; Process; Protein Biosynthesis; Proteins; Proteolysis; Pulmonary Gas Exchange; Rattus; Regulation; Respiratory Diaphragm; Respiratory Muscles; Role; Signal Transduction; Skeletal Muscle; System; Testing; Therapeutic; Ubiquitin; Ventilator; Weaning; Work; adeno-associated viral vector; mTOR protein; multicatalytic endopeptidase complex; novel; novel therapeutics; prevent; research study; therapeutic development; tool; transcription factor

DESCRIPTION (provided by applicant): Mechanical ventilation (MV) is a clinical tool to sustain pulmonary gas exchange in patients that are incapable of maintaining adequate alveolar ventilation. Although MV is often a life-saving intervention, prolonged MV promotes problems in "weaning" patients from the ventilator. While several factors can contribute to difficult weaning, weak inspiratory muscles are a major factor. In this regard, MV results in diaphragmatic inactivity that promotes the rapid onset of inspiratory muscle weakness due to diaphragmatic atrophy and contractile dysfunction (known as ventilator-induced diaphragm dysfunction (VIDD)). Although MV-induced diaphragmatic atrophy occurs due to both increased protein breakdown and decreased protein synthesis, the mechanism(s) that regulate these processes are poorly understood and thus, no clinical therapy exists. Hence, our long-term goal is to identify biological targets that will assist in the development of a therapeutic strategy to preven VIDD and therefore, protect against weaning difficulties. Although numerous signaling events can contribute to VIDD, we predict that the forkhead boxO (FoxO) family of transcription factors are important because they regulate the expression of genes involved in both the ubiquitin-proteasome and the autophagy pathway of proteolysis. Moreover, gene targets of FoxO may also contribute to the depression of protein synthesis. HYPOTHESIS: We will test the hypothesis that activation of FoxO-dependent transcription is required for the decreased protein synthesis, increased expression of proteasome/autophagy genes, and fiber atrophy that occurs in the diaphragm during MV. APPROACH: Our hypothesis will be tested in a well-established rat model of MV. Cause and effect will be determined by using an adeno-associated virus vector for gene delivery to express a dominant negative FoxO to prevent activation of FoxO target genes in the diaphragm during prolonged MV. SPECIFIC AIMS: Aim 1 will establish if FoxO-dependent transcription is essential for the rapid decrease in diaphragmatic protein synthesis that is observed during prolonged MV. Aim 2 will determine if FoxO-dependent transcription is required for the MV-induced increase in the expression of proteasome and autophagy genes along with diaphragmatic atrophy. SIGNIFICANCE: Collectively, this work can provide the foundation for new therapeutic strategies in the prevention of VIDD, a major contributor to the inability to wean patients from the ventilator. PUBLIC HEALTH RELEVANCE: Although mechanical ventilation is a life-saving intervention in patients with acute respiratory failure, prolonged mechanical ventilation promotes weakness in respiratory muscles that can lead to problems in weaning patients from the ventilator. The long-term goal of this project is to identify biological targets that will assist in the development of therapeutic strategy to prevent MV-induced respiratory muscle weakness and protect against weaning difficulties. The results of this study will provide the foundation for new therapeutic strategies for the prevention of MV-induced diaphragmatic weakness, a major contributor to the inability to wean patients from the ventilator.

描述（由申请人提供）：机械通气（MV）是一种临床工具，可维持无法维持足够肺泡通气的患者的肺气交换。尽管MV通常是一种挽救生命的干预措施，但延长的MV促进了呼吸机“断奶”患者的问题。虽然几个因素可能导致断奶，但弱的吸气肌肉是主要因素。在这方面，MV会导致diaphragm肌无活跃，从而促进了由于diaphragmmagmmatotic萎缩和收缩功能障碍（称为呼吸机诱导的隔膜功能障碍（VIDD））引起的灵感肌肉无力发作。尽管MV诱导的diaphragm萎缩是由于蛋白质分解增加和蛋白质合成降低而发生的，但调节这些过程的机制知之甚少，因此不存在临床治疗。因此，我们的长期目标是确定将有助于制定治疗策略的生物学靶标，以预防Vidd，从而防止断奶困难。尽管许多信号传导事件可能有助于VIDD，但我们预测转录因子的叉子Boxo（FoxO）家族很重要，因为它们调节了泛素 - 蛋白酶体和蛋白水解的自噬途径涉及的基因的表达。此外，FOXO的基因靶标也可能有助于蛋白质合成的抑郁。假设：我们将检验以下假设：蛋白质合成降低，蛋白酶体/自噬基因的表达增加以及MV期间diaphragmm的纤维萎缩所必需的FOXO依赖性转录的激活。方法：我们的假设将在建立的MV大鼠模型中进行检验。原因和作用将通过使用腺相关的病毒载体进行基因递送来确定，以表达显性的负FOXO，以防止长期MV期间diaphragm中FOXO靶基因激活。具体目的：AIM 1将确定FOXO依赖性转录是否对于在延长MV期间观察到的diaphragmatic蛋白合成的快速降低至关重要。 AIM 2将确定MV诱导的蛋白酶体和自噬基因表达增加以及diaphragmmagmmatatic萎缩是否需要FOXO依赖性转录。意义：总的来说，这项工作可以为预防Vidd的新治疗策略奠定基础，这是无力从呼吸机中解除患者的主要贡献者。 公共卫生相关性：尽管机械通气是对急性呼吸衰竭患者的挽救生命的干预，但延长的机械通气会促进呼吸肌肉的无力，这可能导致呼吸机断奶患者的问题。该项目的长期目标是确定将有助于制定治疗策略的生物学靶标，以防止MV引起的呼吸道肌肉无力并防止断奶困难。这项研究的结果将为预防MV诱导的diaphragmmantic弱点提供新的治疗策略的基础，这是导致无法从呼吸机断奶患者的主要贡献者。