EXPERIMENTAL EMPHYSEMA--STUDIES ON REMEDIATION

描述(申请人摘要)：我们的长期目标是实现 肺泡和TO形成的分子和细胞解释 将此信息用于肺等疾病的治疗目的 肺气肿。后者以肺泡破坏为特征，属于 在美国，残疾和死亡的主要原因，部分是因为肺 不能更换损坏的肺泡。肺的中心挑战未得到满足 研究-用于治疗目的的肺泡的诱导和形成- 导致肺移植成为治疗肺气肿的唯一方法。 然而，一种范式--非手术廉价的可能性 肺气肿的治疗--由最近的三个观察结果提供：1) 用全反式维甲酸(RA)治疗新生大鼠引起50% 肺泡数增加百分比，但不增加肺容量；2) 相同的治疗方法可防止抑制肺泡的形成和降低 糖皮质激素治疗引起的体质量、比肺泡表面积； 3)维甲酸对弹性酶致大鼠肺气肿的治疗作用 管理废除了人类肺气肿(较大)的结构特征 肺泡减少，肺体积增大，体积缩小得到矫正 表面积)提供了第一个非手术治疗肺气肿和 在人类身上也可能产生类似的影响。我们的具体目标是1) 使用无偏的形态计量学方法来检验这样的假设 RA将取消弹性蛋白酶诱导的非人类肺气肿的关键发现 灵长类；2)利用分子生物学技术启动系统的 致病基因鉴定方法的探讨 非人灵长类动物的肺泡；3)使用形态计量学方法测试 假设，在非人灵长类动物中，细胞成分 肺泡壁，以及肺泡上皮表面积和肺泡上皮面积之间的平衡 肺泡毛细血管表面积是弹性蛋白酶诱导的肺气肿的变化 经RA治疗后恢复正常。我们相信我们可以 实现这些具体目标是因为我们在以下方面有相当丰富的经验 形态计量学，2)制造并逆转大鼠肺气肿，3)成功 熟悉所有必要的分子生物学程序，以及4) 在非人类灵长类动物身上产生了肺气肿。

DESCRIPTION (Applicant's abstract): Our long range goal is to achieve a molecular and cellular explanation for the formation of an alveolus and to use this information for therapeutic purposes in diseases such as pulmonary emphysema. The latter, characterized by alveolar destruction, is among the leading causes of disability and death in U.S., in part, because the lung fails to replace destroyed alveoli. A central unmet challenge of lung research - the induction and formation of alveoli for therapeutic purposes - has led to lung transplantation being the only remediation for emphysema. However, a paradigm - the possibility of non-surgical inexpensive remediation of emphysema - is offered by three recent observations: 1) treatment of newborn rats with all trans retinoic acid (RA) causes a 50 percent increase in alveolar number without increasing lung volume; 2) identical treatment prevents the inhibition of alveolar formation and low body mass specific alveolar surface area caused by corticosteroid treatment; 3) treatment with RA of adult rats previously made emphysematous by elastase administration abrogates the structural features of human emphysema (larger and fewer alveoli, increased lung volume, and diminished volume corrected surface area) providing the first non-surgical remediation of emphysema and the possibility of a similar effect in humans. Our specific aims are 1) to use unbiased morphometric methods to test the hypothesis that treatment with RA will abrogate key findings of elastase induced emphysema in a non-human primate; 2) to use molecular biology techniques to initiate a systematic approach to the identification of genes responsible for the formation of alveoli in a non-human primate; 3) to use morphometric methods to test the hypothesis that, in a non-human primate, the cellular composition of the alveolar wall, and the balance between alveolar epithelial surface area and alveolar capillary surface area are changes in elastase-induced emphysema and are returned to normal by treatment with RA. We believe that we can achieve these specific aims because we have 1) considerable experience with morphometry, 2) produced and reversed emphysema in rats, 3) successful experience with all the necessary molecular biology procedures, and 4) produced emphysema in a non-human primate.