Adiponectin inhibits activation and injury of lung endothelium

描述（由申请人提供）：本资助研究由脂肪细胞来源的激素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具有滋补性抑制内皮细胞活化和限制内皮细胞损伤（如高氧）引起的损伤的作用。该提案将利用广泛的遗传工具（如脂联素和脂联素受体缺陷小鼠）和试剂（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。Aim 1的研究将确定介导脂联素对肺内皮影响的寡聚物组分和关键结构域，并阐明脂联素对肺内皮的下游信号通路。Aim 2的研究旨在验证脂联素通过激活肺内皮的抗炎和细胞保护过程来减轻高氧肺损伤的假设。最后，Aim 3的研究将利用体外和体内工具来鉴定介导脂联素在肺中的作用的重要脂联素受体。综上所述，这笔资助的研究将确定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，并为合理设计未来的临床研究奠定基础，研究APN在人类肺部疾病中的作用。

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.