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Adiponectin inhibits activation and injury of lung endothelium

脂联素抑制肺内皮细胞的活化和损伤

基本信息

批准号：
8186653
负责人：
Ross S Summer
金额：
$ 40.88万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8186653
关键词：
Acute Lung Injury Adenovirus Vector Adipocytes Adipose tissue Advanced Practice Nurse Agonist Animals Anti-Inflammatory Agents Anti-inflammatory Apoptotic Area Attenuated Binding Biological Biology Blood Vessels Body fat Cells Clinical Trials Complex Critical Illness Data Distal E-Selectin Endocrine Glands Endothelial Cells Endothelium Epidemic Etiology Foundations Future Gene Deletion Genetic Grant H-Cadherin Homeostasis Hormones Human Hyperoxia In Situ Hybridization In Vitro Infiltration Inflammatory Inflammatory Response Injury Investigation Knock-out Laboratories Lung Lung Inflammation Lung diseases Mediating Metabolism Molecular Molecular Weight Mus Obesity Patients Phenotype Play Prevention therapy Process Proteins Pulmonary artery structure Reagent Recombinants Research Role Serum Signal Pathway Site Small Interfering RNA Stream Structure of parenchyma of lung Surface Testing Up-Regulation Vascular Diseases adipokines adiponectin cell injury design gain of function in vivo interest knock-down lung injury mortality novel pressure prevent pulmonary artery endothelial cell receptor research study response to injury tool vascular inflammation

项目摘要

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. PUBLIC HEALTH RELEVANCE: This grant introduces the novel concept that an adipocyte-derived hormone called adiponectin regulates homeostatic suppression of lung endothelium and mitigates lung injury originating from endothelial cell damage. Studies in this proposal aim to elucidate the molecular mechanisms mediating adiponectin's effects on murine lung endothelium in order to identify new strategies for developing novel therapies for prevention and treatment of human lung vascular disease.

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。公共卫生相关性：这项资助引入了一种新的概念，即一种称为脂联素的脂肪细胞衍生激素调节肺内皮细胞的稳态抑制，减轻内皮细胞损伤引起的肺损伤。本研究旨在阐明脂联素对小鼠肺内皮细胞作用的分子机制，为开发防治人类肺血管疾病的新疗法提供新的策略。