Adiponectin inhibits activation and injury of lung endothelium

描述（由申请人提供）：本基金研究脂肪细胞衍生激素脂联素介导的肺和脂肪组织之间的分子相互作用。脂联素已显示在鼠肺中起作用以张力性地抑制内皮细胞活化并限制源自内皮细胞损伤的损伤（例如高氧）。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）进行脂联素在肺血管稳态中的作用的第一次全面检查。目的1的研究将确定介导脂联素对肺内皮作用的寡聚体组分和关键结构域，并将阐明脂联素对肺内皮作用的下游信号通路。目的2中的研究旨在检验脂联素通过激活肺内皮上的抗炎和细胞保护过程减轻高氧肺损伤的假设。最后，目标3中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。总之，这项研究将确定APN调节肺血管过程的分子机制，以期确定肺血管生物学研究的新途径，并为未来研究APN在人类肺部疾病中的临床研究的合理设计奠定基础。

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.