REMEDIATION OF EMPHYSEMA--MECHANISMS, CHARACTERISTICS

描述：该申请人长期以来一直对 出生后肺泡形成的生物学 发展最近，他已经证明，维甲酸（RA）不 不仅促进大鼠肺泡的出生后发育， 提供了一个实验模型中的组织变化的补救措施， 成年大鼠的肺气肿。为了进一步研究这一发现，他的具体 目的是：1）利用差异显示（DD）和差异筛选， 作为系统搜索大鼠肺部基因的组成部分， 在RA期间肺泡形成中的独特和基本功能- 消除弹性蛋白酶诱导的肺气肿。选择的类似基因将是 在小鼠中克隆和"敲除"， 确定是否存在以下任何变更：a）分隔 B）在新生小鼠中的气体交换区的后分隔区; 肺泡数量增加，或c）消除弹性蛋白酶诱导的 肺气肿2)使用形态测量程序来检验假设a） 在弹性蛋白酶诱导的肺气肿大鼠中， 在用RA治疗后减少但增加; B）RA- 弹性蛋白酶产生的肺气肿在治疗后持续存在 c）治疗Tsk小鼠（其具有 由于低血清和肺抗弹性蛋白酶活性引起的肺气肿）与单独的RA， 再加上蛋白酶抑制剂，就能消除肺气肿我们相信我们的 初步数据和有据可查的主管领域， 参与这项建议的人证明了可行性和可能的成功 我们追求一种新的模式--药物补救 了解肺泡的分子基础， 阵

DESCRIPTION: This applicant has had a long-standing interest in the biology of the formation of pulmonary alveoli during post-natal development. Recently, he has demonstrated that retinoic acid (RA) not only promotes the post-natal development of alveoli in the rat but also provides remediation of the tissue changes in an experimental model of emphysema in adult rats. To investigate this finding further, his specific aims are: 1) to use differential display (DD) and differential screening, as components of a systematic search for genes that in rat lung have unique and essential functions in the formation of alveoli during RA- abrogation of elastase-induced emphysema. Selected analogous genes will be cloned and "knocked-out" in mice and morphometric procedures use to determine if there is an alteration of any of the following: a) septation of the gas-exchange region in the newborn mouse; b) the post-septational increase in alveolar number, or c) abrogation of elastase-induced emphysema. 2) To use morphometric procedures to test the hypothesis a) that in rats with elastase-induced emphysema the long's diffusion capacity is diminished but increased after treatment with RA; b) that the RA- induced abrogation of elastase produced emphysema persists after treatment with RA is stopped; and c) that treatment of Tsk mice (which have emphysema due to low serum and lung anti-elastase activity) with RA alone, and with a protease inhibitor, will abrogate the emphysema. We believe our preliminary data and the well documented areas of competence of those involved in this proposal demonstrate the feasibility and likely success of our pursuit of a new paradigm--the pharmacological remediation of emphysema fostered by understanding the molecular basis of alveolus formation.