Molecular Regulation of LRAT and CYP26 in Lung and Liver

描述(申请人提供)：饮食来源的维生素A(视黄醇)首先以视黄酸酯(RE)的形式储存在组织中，它通过水解和受控的氧化代谢产生生物活性的维甲酸，包括维甲酸(RA)。维甲酸是细胞分化的重要调节因子。对于肺来说，RA对于正常的出生后肺泡发育和成熟是至关重要的。RA是唯一能诱导肺泡间隔(间隔突起)的小分子，而肺泡间隔是形成完整呼吸能力所必需的。RA还在成人肺气肿疾病和手术后组织再生的模型中显示出治疗效果。我们的中心假设是：由维生素A及其激素样代谢物全反式RA组成的营养-代谢物组合VARA将协同作用，促进新生儿肺中稀土的形成。VARA诱导的RE形成可能为内源性类维A酸的产生创造有利条件，并促进肺泡重塑(间隔)。在目标1中，我们将通过检查：(1a)几种维甲酸与视黄醇协同作用的有效性；(1b)在RA存在的情况下，肺对乳糜粒中新吸收的VA的摄取是否增加；以及(1c)炎症(肺不成熟的伴随因素)是否改变或减弱我们在接受VARA治疗的新生儿肺中观察到的协同反应，来检验VARA协同增加肺中RE的假设。在目标2中，我们将通过对肺和肝脏中依赖时间的基因表达和关键因子(LRAT、CYP26B1和DHRS3，一种视网膜还原酶)的定位的研究，来检验VARA治疗的功能结果。最后，在这个目的中，还将测试VARA是否在糖皮质激素抑制的肺泡间隔的临床相关模型中改善肺成熟。这两个结合的目标将提供关于VARA促进细胞分化和器官成熟的潜力的新知识，并改善受损的出生后肺发育。公共卫生相关性：维生素A和维甲酸(VARA)的结合，通过其增加肺中稳定的视黄酸酯的能力，可能会建立有利于肺成熟和修复的条件。因此，VARA似乎具有预防新生儿支气管肺发育不良、治疗晚年肺损伤的临床潜力，并有可能用于癌症的化学预防。通过在动物模型中揭示维生素A、RA和VARA对肺中基因和酶的分子效应，这项研究将确定VARA是否可以作为治疗慢性肺部疾病高危新生儿以及修复成人肺损伤或进行化学预防的进一步临床前试验。

DESCRIPTION (provided by applicant): Diet-derived vitamin A (retinol) is first stored in tissues as retinyl esters (RE), which, through hydrolysis and controlled oxidative metabolism generate bioactive retinoids, including retinoic acid (RA). Retinoic acid is a critical regulator of cell differentiation. For the lungs, RA is crucial for normal postnatal alveolar development and maturation. RA is the only small molecule shown to induce lung alveolar septation (septal outgrowth), which is required for development of full respiratory capacity. RA also has shown therapeutic benefits in models of adult lung emphysematous disease and tissue regeneration after surgery. Our central hypothesis is: A nutrient-metabolite combination , VARA, comprised of vitamin A and its hormone-like metabolite all-trans-RA, will act synergistically to promote RE formation in the lungs of neonates. VARA-induced RE formation may establish conditions beneficial for endogenous production of retinoids, and facilitate alveolar remodeling (septation). In Aim 1 we will test the hypothesis that VARA synergistically increases RE in the lungs by examining: (1a) the effectiveness of several retinoids to synergize with retinol; (1b) whether the uptake by the lungs of newly absorbed VA contained in chylomicrons is increased in the presence of RA; and (1c) whether inflammation, a concomitant factor in lung immaturity, modifies or attenuates the synergistic response we have observed in the lungs of neonates treated with VARA. In Aim 2 we will examine functional outcomes of VARA treatment, through studies of time-dependent gene expression and localization of key factors (LRAT, CYP26B1, and DHRS3, a retinal reductase) in the lungs and liver. Finally, in this aim will also test whether VARA improves lung maturation in a clinically relevant model of glucocorticoid-inhibited alveolar septation. These two integrated aims will provide new knowledge regarding the potential of VARA to promote cellular differentiation and organ maturation, and ameliorate impaired postnatal lung development. PUBLIC HEALTH RELEVANCE: The combination of vitamin A and retinoic acid, VARA, through its ability to increase a stable pool of retinyl esters in the lungs, may establish conditions that are conducive to lung maturation and repair. VARA thus appears to have clinical potential for preventing neonatal bronchopulmonary dysplasia, treating lung damage later in life, and, potentially, for cancer chemoprevention. By revealing the molecular effects of vitamin A, RA, and VARA on genes and enzymes in the lungs in an animal model, this research will establish whether VARA warrants further preclinical testing as a therapy for newborns at high risk of chronic lung disease, and for repair of lung injury or chemoprevention in adults.