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INFLUENCE OF STRETCH ON LUNG GROWTH & RESPONSE TO INJURY

伸展对肺部生长的影响

基本信息

批准号：
3362097
负责人：
MARTIN POST
金额：
$ 7.67万
依托单位：
HOSPITAL FOR SICK CHLDRN (TORONTO)
依托单位国家：
美国
项目类别：
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

项目摘要

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肺生长的调节，损伤后再生肺生长，在体内和体外，蛋白质生长因子的表达和作用。大量证据这表明，在胎儿和出生后的生活，有一个强大的肺所受到的机械力之间的关联和肺细胞有丝分裂率。根据这些证据，从这个实验室的广泛的初步工作，我们建议这两个相关假设： 1.腺泡的发育是由自分泌和分泌的肺细胞旁分泌生长因子，以响应“拉伸”发生在正常呼吸活动期间，应答 2.这一过程在急性全身性肺损伤期间被阻止，随后的修复和再生代表了一种扩增，恢复正常进程。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的个体发生，新生大鼠肺生长因子的北方印迹和狭缝印迹分析，它们的受体和相关的原癌基因将与测量进行比较，细胞增殖。 2.为了确定“拉伸”对胎肺细胞生长因子、受体及原癌基因表达体外基于目标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。这两个系统将在静态条件下进行研究，伸展。 3.目的：探讨氧疗对急性肺损伤的影响，通过对生长因子、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.为了确定急性损伤氧气，然后是恢复，修改了“拉伸”对生长的影响胎儿肺组织中生长因子、生长因子受体及原癌基因表达的研究体外细胞