ALVEOLUS FORMATION--MORPHOMETRIC AND MOLECULAR STUDIES

描述（改编自申请人摘要）：长期目标是了解肺泡形成的调控，以便这些信息可用于治疗目的。在缺乏诱导人类肺泡形成的药理学手段的情况下，肺移植仍然是治疗肺泡形成发育缺陷的疾病的唯一补救方法，例如支气管肺发育不良或肺泡破坏导致的肺泡缺陷，例如肺气肿。为了确保和促进分子诱导肺泡形成，除了已经在啮齿动物中实现的全反式维甲酸（RA）治疗之外，还需要对自发和RA诱导肺泡形成的机制以及RA治疗肺泡缺陷肺的程度和功能影响有一个基本的了解。这一建议是基于以下研究结果：RA 1)诱导新生大鼠肺泡形成，并阻止皮质类固醇激素对肺泡形成的抑制；2)增加断奶后大鼠肺泡形成；3)部分消除先前糖皮质类固醇对断奶后大鼠肺泡形成的抑制；4)在自发分隔失败的成年紧皮小鼠中启动分隔。5)消除了先前通过注入弹性蛋白酶使成年大鼠肺气肿形成的人肺气肿和实验性肺气肿的主要特征。这一建议也基于其他许多人的工作，这些工作导致了脂质间质细胞，维生素A的肺储存位点，作为组织中心，通过释放类维生素A来发出信号，表明肺泡形成的开始、停止和代谢调节间隔，其他细胞以适当的基因表达变化做出反应。因此，在大鼠和小鼠的研究中，具体目标集中在a)阐明参与调节肺泡形成的类视黄醇受体，b)评估O2扩散途径的解剖成分对实验性或自发性分离失败的大鼠和小鼠RA治疗的反应，以及c)培养脂质间质细胞对类视黄醇释放的调节以及这些细胞对共培养肺微血管细胞的影响。本研究将提供重要的生物学和临床信息，进一步阐明类视黄醇受体在肺泡形成诱导和停止过程中的作用；进一步阐明类视黄醇在临床上的作用条件和程度；进一步推进以治疗为目的的诱导肺泡形成的新范式。

DESCRIPTION (Adapted from the applicant's abstract): The long term goal is to understand the regulation of the formation of pulmonary alveoli so this information may be used for therapeutic purposes. In the absence of pharmacological means of inducing alveolus formation in humans, lung transplantation remains the only remediation for diseases in which there is a developmental deficit of alveolus formation, e.g. bronchopulmonary dysplasia or a deficit of alveoli due to their destruction, e.g. emphysema. To insure and facilitate a molecular induction of alveolus formation, beyond that already achieved in rodents by treatment with all-trans retinoic acid (RA), a fundamental understanding of the mechanism(s) of the spontaneous and RA-induced formation of alveoli, and the extent and functional effect of RA treatment on alveolar-deficient lungs, are required. This proposal is based on work showing RA 1) induces the formation of alveoli in newborn rats and prevents the inhibition of alveolus formation by a corticosteroid hormone, 2) increases alveolus formation in postweaning rats, 3) partially abrogates the prior glucocorticosteroid inhibition of alveolus formation in postweaning rats, 4) initiates septation in adult tight-skin mice in which there is failed spontaneous septation, and 5) abrogates key features of human and experimental emphysema in adult rats previously made emphysematous by the instillation of elastase. This proposal is also based on the work of many others that has led to the notion that lipid interstitial cells, lung storage sites for vitamin A, serve as organizing centers to signal the onset, cessation, and metabolically regulated spacing of alveolus formation by the release of retinoids, to which other cells respond with appropriate changes in gene expression. Therefore the specific aims, for work on rats and mice, focus on a) the explication of the retinoid receptors involved in regulating alveolus formation, b) an assessment of the response of the anatomical components of the O2 diffusion pathway to RA treatment of rats and mice that have experimental or spontaneous failed septation, and c) the regulation of release of retinoids by cultured lipid interstitial cells and the effect of these cells on co-cultured pulmonary microvascular cells. The proposed work will 1) provide important biological and clinical information by further explicating the retinoid receptors involved in the induction and cessation of alveolus formation, 2) further elucidate the conditions and the extent to which retinoids might be useful clinically, and 3) further advance the new paradigm of the induction of alveolus formation for therapeutic purposes.