Apoptotic Signaling Induces Hyperpermeability Following

细胞凋亡信号传导导致通透性过高

• 批准号: 7100474
• 负责人: ED W CHILDS
• 金额: $ 13.61万
• 依托单位: SCOTT AND WHITE MEMORIAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7100474
• 关键词: apoptosis; atomic force microscopy; biological signal transduction; cell adhesion; cellular pathology; cysteine endopeptidases; cytochrome c; enzyme activity; free radical oxygen; hemorrhagic shock; immunofluorescence technique; immunoprecipitation; intercellular connection; intravital microscopy; laboratory rat; protein localization; site directed mutagenesis; transfection; transfection /expression vector; vascular endothelium permeability

DESCRIPTION (provided by applicant): This application describes a comprehensive vascular research program designed to develop Dr. Childs into an independent investigator. Through course work in molecular biology, research design, and statistics, he will acquire the necessary analytical skills to achieve this goal. He will also be required to attend several annual conferences and a monthly journal club. An Advisory Board of experienced investigators in vascular and cellular biology has been established for Dr. Childs to obtain hands on experience in laboratory techniques. Development of grantsmanship is emphasized throughout the duration of the K01 award, beginning with applications for local funds, graduating to an American Heart Association grant, and culminating in a R01 submission to the NIH in the third year of this award. The research plan focuses on the regulation of endothelial cell-cell adherens junctions to prevent microvascular hyperpermeability following hemorrhagic shock. Fluid loss from the circulation is a major factor in compromising cardiovascular homeostasis following trauma, burns, sepsis and hemorrhagic shock. Preventing microvascular barrier opening or reestablishing barrier function is crucial in limiting the deleterious effects on the cardiovascular, pulmonary and nervous systems. Hemorrhagic shock-induced hyperpermeability results in alteration of the endothelial cell-cell adherens junction complex. Site-specific alterations in the structure of (3-catenin have been implicated as an important modulator of these junctions. The applicant hypothesizes that hemorrhagic shock-induced activation of caspases results in a (3- catenin-dependent modification of endothelial adherens junction. To address this hypothesis, the applicant proposes two interlocking specific aims: (1) define the relationship between the apoptotic cascade and hemorrhagic shock-induced hyperpermeability and (2) identify the interaction(s) of caspase-3 with the adherens junction complex. Intravital microscopy with a novel in vivo protein transfection technique in parallel with cell monolayers will be utilized to determine changes in microvascular hyperpermeability. Atomic force microscopy will be used to assess endothelial cell adhesive forces. (End of Abstract)

描述（由申请人提供）：