REMEDIATION OF EMPHYSEMA--MECHANISMS, CHARACTERISTICS

肺气肿的治疗——机制、特点

• 批准号: 2600755
• 负责人: DONALD John MASSARO
• 金额: $ 33.96万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2600755
• 关键词: RNase protection assay; all trans retinol; cell growth regulation; computer assisted sequence analysis; elastases; electron microscopy; electroporation; emphysema; gene expression; gene targeting; laboratory mouse; laboratory rat; lung alveolus; molecular biology; molecular cloning; northern blottings; nucleic acid sequence; polymerase chain reaction; protease inhibitor; regeneration; respiratory disorder chemotherapy; respiratory pharmacology; southern blotting; statistics /biometry; tissue /cell preparation; vitamin therapy

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.

描述：此申请者长期以来一直对 出生后肺泡形成的生物学研究 发展。最近，他证明了维甲酸(RA)不是 不仅促进大鼠肺泡的出生后发育，而且还 在实验模型中提供对组织变化的补救 成年大鼠的肺气肿。为了进一步调查这一发现，他的具体 目的是：1)使用差异显示(DD)和差异筛选， 作为系统寻找基因的组成部分，在大鼠肺中有 类风湿性关节炎时肺泡形成过程中独特而重要的功能 消除弹性酶诱导的肺气肿。选定的相似基因将是 小鼠的克隆和“敲除”和形态计量学程序用于 确定是否有以下任何变化：a)隔膜 新生小鼠的气体交换区；b)隔膜后 肺泡数增加，或c)弹性蛋白酶诱导的肺泡数减少 肺气肿。2)使用形态计量学程序检验假设a) 弹性酶诱导的肺气肿大鼠Long‘s扩散能力的研究 在RA治疗后减少但增加；b)RA- 弹性蛋白酶引起的肺气肿在治疗后持续被诱导消除 停止使用RA；以及c)治疗TSK小鼠(它们有 由于血清和肺抗弹力酶活性低而导致的肺气肿)单独患有RA， 用一种蛋白水解酶抑制剂，可以消除肺气肿。我们相信我们的 初步数据和有充分记录的这些人的能力领域 参与这项提议证明了其可行性和可能取得的成功 我们追求一种新的范式--药物治疗 通过了解肺泡的分子基础而形成肺气肿 队形。