Hypoxia Disrupts the Alveolar Barrier: Role of Claudins

缺氧破坏肺泡屏障：克劳丁的作用

• 批准号: 7618489
• 负责人: ALEJANDRO Pierre COMELLAS
• 金额: $ 13.33万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618489
• 关键词: Adult Respiratory Distress Syndrome; Affect; Alveolar; Alveolus; Back; Cell Communication; Cell membrane; Cellular Structures; Congestive Heart Failure; Data; Development; Disease; Edema; Endocytosis; Endosomes; Environment; Epithelial; Epithelial Cells; Event; Gases; Hypoxia; Lung; Lysosomes; Mitochondria; Oxygen; Patients; Phosphorylation; Protein Kinase C; Proteins; Public Health; Pulmonary Edema; Reactive Oxygen Species; Regulation; Research; Respiratory Failure; Risk; Role; System; Testing; Tight Junctions; Ubiquitin; Vertebral column; alveolar epithelium; bone; citrate carrier; claudin 3; design; improved; junctional adhesion molecule; lung injury; multicatalytic endopeptidase complex; novel strategies; research study; trafficking

DESCRIPTION (provided by applicant): The alveolar epithelial barrier needs to be disrupted for developing alveolar edema. The integrity of this barrier is dependent on the presence of tight junctions (TJs); which contribute to keep cell interactions intact. Accordingly their disruption could manifest in the development of alveolar edema and impared gas exchange. During lung injury and pulmonary edema a hypoxic environment is present at the alveolus which could contribute to further disruption of the alveolar epithalial barrier, specifically the tight junctions. These cell structures are formed by multiple proteins, among them the claudins which are considered the backbones of the tight junctions. The effect of hypoxia on alveolar epithelial cells (AECs) tight junctions have not been elucidated. We propose to determine the effect of hypoxia on the alveolar epithelial barrier specifically on the claudin proteins. We propose three inter-related specific aims: 1) to determine whether hypoxia disrupts the alveolar barrier via endocytosis of claudin 3 and 4 from the plasma membrane into intracellular compartments of alveolar epithelial cells. 2) To determine whether hypoxia, via mitochondrial reactive oxygen species, stimulates Protein Kinase C (PKC), thus increasing the phosphorylation of claudin- 3 and 4 and promoting their endocytosis. 3) To determine whether during hypoxia the ubiquitin-conjugating system is necessary for the trafficking and /or degradation of claudin 3 and 4.We expect that the data generated from these experiments will ultimately help with the understanding of mechanisms by which the alveolar epithelium is affected by hypoxia and the design of novel strategies to treat patients who are at risk to develop disruption of the alveolar epithelial barrier, such as in ARDS Relevance of this research to public health: Disruption of the alveolar epithelium barrier causes pulmonary edema. Understanding how to block its disruption can potentially improve survival in disease states such as ARDS and congestive heart failure.

描述（由申请人提供）：