IGF AXIS IN PULMONARY VASCULAR REMODELING

IGF 轴在肺血管重塑中的作用

• 批准号: 2415461
• 负责人: SUSAN F TOWNSEND
• 金额: $ 8.4万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2415461
• 关键词: antisense nucleic acid; cow; disease /disorder model; embryo /fetus; exoribonucleases; fibroblasts; gene expression; growth /development; hemodynamics; immunocytochemistry; in situ hybridization; newborn animals; perinatal; polymerase chain reaction; pulmonary circulation; pulmonary hypertension; respiratory hypoxia; tissue /cell culture; vascular endothelium; western blottings

The role of IGF-II and IGF-BP's in the dramatic pulmonary vascular remodeling associated with neonatal pulmonary hypertension will be studied. The fibroproliferative response in this disease characterizes the neonate, and may represent a unique developmental susceptibility to injury at a time of marked changes in circulatory physiology and vessel maturation. Our preliminary data suggest a role for increased expression of IGF-II in the vascular proliferative response. IGF-BPs produced by vascular wall cells play a central role in localizing and modulating IGF actions at the cellular level. We hypothesize that increased IGF-II expression in the pulmonary vessel wall is a critical modulator of the vascular proliferative response in neonatal hypoxic pulmonary hypertension. We propose that increased IGF-II expression in neonatal pulmonary hypertension reflects persistence of a fetal pattern of gene expression in the perinatal period, associated with altered expression and accumulation of specific IGF-BP's. We postulate that altered expression of IGF-II and IGF-BP's is regulated by hypoxia in vitro, with different effects on the adventitial fibroblast and vascular smooth cell. The goals are: 1) to evaluate the normal developmental changes in IGF-II and IGF-BP expression in the pulmonary circulation during late fetal and early neonatal life, and how these are affected by developing hypoxic pulmonary hypertension in the newborn, and 2) to examine directly how hypoxia alters expression of IGF-II and IGF-BPs in fetal, neonatal, and hypertensive vascular wall cells in vitro.

IGF-II和IGF-BP在急性肺血管病中的作用 与新生儿肺动脉高压相关的重塑将是 研究了 这种疾病的纤维增生反应的特征是 新生儿，并可能代表一个独特的发展易感性， 在循环生理和血管发生显著变化时发生损伤 成熟 我们的初步数据表明， IGF-II在血管增殖反应中的作用。 IGF-BP生产商 血管壁细胞在定位和调节IGF中起重要作用 在细胞水平上的作用。 我们假设IGF-II的增加 在肺血管壁中的表达是一个关键的调节剂， 新生儿缺氧性肺血管增生反应 高血压 我们认为IGF-II在新生儿中的表达增加， 肺动脉高压反映了胎儿型基因的持续存在 在围产期表达，与表达改变相关 和特定IGF-BP的积累。 我们假设， IGF-II和IGF-BP的表达在体外受缺氧调节， 对血管外膜成纤维细胞和血管平滑肌细胞的影响不同。 本研究的目的是：1）评价正常发育过程中IGF-II的变化 和IGF-BP在胎儿晚期肺循环中的表达， 早期新生儿的生活，以及这些是如何影响发展缺氧 新生儿肺动脉高压，2）直接检查如何 缺氧改变胎儿、新生儿和新生儿IGF-II和IGF-BPs表达 体外培养高血压血管壁细胞。