INFLUENCE OF STRETCH ON LUNG GROWTH & RESPONSE TO INJURY

伸展对肺部生长的影响

• 批准号: 3362096
• 负责人: MARTIN POST
• 金额: $ 7.52万
• 依托单位: HOSPITAL FOR SICK CHLDRN (TORONTO)
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1992-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3362096
• 关键词: cell growth regulation; developmental genetics; embryo /fetus cell /tissue; gene expression; genetic transcription; gestational age; growth /development; growth factor; growth factor receptors; immunocytochemistry; in situ hybridization; injury; laboratory rat; lung; newborn animals; oncogenes; protooncogene; pulmonary stretch receptors; respiratory oxygen; western blottings

We propose to study the regulation of normal fetal lung growth, and of post-injury regenerative lung growth, in vivo and in vitro, with respect to the expression and effects of protein growth factors. Extensive evidence suggest that in both fetal and postnatal life, there is a strong association between the mechanical forces to which the lung is subjected and the rate of pulmonary cellular mitosis. Based on this evidence and on extensive preliminary work from this laboratory, we propose to these two related hypotheses: 1. That acinar development is mediated by the release of autocrine and parcrine growth factors by lung cells, in response to "stretch" incurred during normal breathing activity, with resultant cellular oncogene responses. 2. That this process is arrested during acute generalized lung injury, and that subsequent repair and regeneration represents an amplification or reactivation of the normal process. These hypothese will be tested in four specific aims: 1. To define growth factor, growth factor receptor and proto-oncogene ontogeny in the fetal and neonatal rat lung. Northern blot and slot blot analyses of growth factors, their receptors, and related proto-oncogenes will be compared with measures of cell proliferation. 2. To determine the influence of "stretch" on growth factor, receptor and proto-oncogene expression of fetal lung cells in vitro. Based upon the results from aim 1, we will study these endpoints in lung cells cultured singly and in a three dimensional multi-cell system. Both systems will be studied under static conditions and after exposure to stretch. 3. To define the effect of acute lung injury with oxygen followed by recovery on growth factor, growth factor receptor and proto-oncogene expression in the neonatal rat lung. 4. To define how acute injury with oxygen, followed by recovery, modifies the influence of "stretch" on growth factor, growth factor receptor and proto-oncogene expression of fetal lung cells in vitro.

我们建议研究正常胎儿肺部生长的调节，以及 损伤后肺再生再生，在体内和体外，关于 蛋白质生长因子的表达和作用。大量证据 表明在胎儿和出生后的生活中，存在着强烈的 肺所承受的机械力之间的关联 和肺细胞有丝分裂率。基于此证据和 该实验室进行了大量的前期工作，我们向这两个建议 相关假设： 1. 腺泡的发育是由自分泌和 肺细胞分泌生长因子，以应对“拉伸” 在正常呼吸活动期间，产生细胞癌基因 回应。 2. 该过程在急性全身性肺损伤期间被阻止，并且 随后的修复和再生代表着放大或 重新启动正常进程。 这些假设将在四个具体目标中得到检验： 1. 定义增长 因子、生长因子受体和原癌基因个体发育在胎儿和 新生大鼠肺。生长因子的 Northern 印迹和狭缝印迹分析， 他们的受体和相关原癌基因将与测量结果进行比较 细胞增殖。 2. 确定“拉伸”对的影响 胎肺细胞生长因子、受体及原癌基因的表达 体外。根据目标 1 的结果，我们将研究这些终点 在单独培养的肺细胞和三维多细胞系统中。 这两个系统都将在静态条件下和暴露于环境后进行研究 拉紧。 3. 确定氧气对急性肺损伤的影响 通过生长因子、生长因子受体和原癌基因的恢复 在新生大鼠肺中的表达。 4. 定义急性损伤如何 氧气，然后是恢复，改变了“拉伸”对生长的影响 胎肺因子、生长因子受体及原癌基因的表达 体外细胞。