INFLUENCE OF STRETCH ON LUNG GROWTH & RESPONSE TO INJURY

伸展对肺部生长的影响

• 批准号: 3362095
• 负责人: MARTIN POST
• 金额: $ 7.75万
• 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/3362095
• 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生长的调节，以及 损伤后再生性肺生长，体内和体外 蛋白质生长因子的表达和作用。广泛的证据 这表明，在胎儿和出生后的生活中，都有强烈的 肺所受的机械力之间的联系 以及肺细胞有丝分裂的比率。基于这一证据和 来自这个实验室的广泛的前期工作，我们向这两个人建议 相关假设： 1.腺泡发育是通过释放自分泌和 肺细胞分泌生长因子，因“拉伸”而招致 在正常的呼吸活动中，以及由此产生的细胞癌基因 回应。 2.在急性全身性肺损伤期间，这一过程被阻止，以及 随后的修复和再生代表着放大或 重新激活正常流程。 这些假设将在四个具体目标中得到检验：1.定义增长 胎儿和胎儿的因子、生长因子受体和原癌基因发生 新生大鼠肺。生长因子的Northern印迹和狭缝印迹分析， 它们的受体和相关原癌基因将与措施进行比较 细胞增殖率。2.确定“伸展”对 胎肺细胞生长因子、受体和原癌基因的表达 在试管中。基于目标1的结果，我们将研究这些端点 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在 伸展一下。3.明确氧对急性肺损伤的影响 通过恢复生长因子、生长因子受体和原癌基因 在新生大鼠肺组织中的表达。4.定义急性损伤如何与 氧气，然后是恢复，改变了“拉伸”对生长的影响 胎肺生长因子、生长因子受体和原癌基因的表达 体外培养的细胞。