Adiponectin inhibits activation and injury of lung endothelium

描述(申请人提供)：这项资助研究脂肪细胞衍生荷尔蒙脂联素介导的肺和脂肪组织之间的分子相互作用。脂联素已被证明在小鼠肺中作用于张力抑制内皮细胞激活和限制由内皮细胞损伤(如高氧)引起的损伤。这项建议将利用广泛的遗传工具(例如脂联素和脂联素受体缺陷小鼠)和试剂(例如重组脂联素蛋白、腺病毒载体)来首次全面检查脂联素在肺血管稳态中的作用。目标1的研究将确定脂联素对肺内皮细胞影响的低聚组分和关键结构域，并将阐明脂联素对肺内皮细胞的下游信号通路。AIM 2中的研究旨在验证脂联素通过激活肺内皮细胞上的抗炎和细胞保护过程来减轻高氧所致肺损伤的假设。最后，AIM 3的研究将利用体外和体内工具来确定重要的脂联素受体介导脂联素在肺中的作用。综上所述，这项拨款的研究将确定APN调节肺血管过程的分子机制，希望找到肺血管生物学研究的新途径，并为未来合理设计APN在人类肺部疾病中的临床研究奠定基础。

DESCRIPTION (provided by applicant): This grant studies the molecular interaction between lung and adipose tissue mediated by the adipocyte-derived hormone adiponectin. Adiponectin has been shown to act in murine lung to tonically inhibit endothelial cell activation and to limit injury originating from endothelial cell damage (e.g. hyperoxia). This proposal will utilize a broad range of genetic tools (e.g. adiponectin and adiponectin receptor deficient mice) and reagents (e.g. recombinant adiponectin protein, adenoviral vectors) to perform the first comprehensive examination of adiponectin's role in lung vascular homeostasis. Studies in Aim 1 will identify the oligomeric fractions and key structural domains mediating adiponectin's effects on lung endothelium and will elucidate the down-stream signaling pathways of adiponectin on lung endothelium. Studies in Aim 2 are designed to test the hypothesis that adiponectin mitigates lung injury to hyperoxia by activating anti- inflammatory and cyto-protective processes on lung endothelium. Finally, studies in Aim 3 will utilize in vitro and in vivo tools to identify the important adiponectin receptor mediating adiponectin's effects in lung. Taken together, studies in this grant will identify the molecular mechanisms by which APN regulates lung vascular processes in the hope of identifying new avenues of research in lung vascular biology and laying the foundation for the rational design of future clinical investigations examining APN in human lung disease.