Molecular Regulation of LRAT and CYP26 in Lung and Liver

描述（由申请人提供）：膳食来源的维生素A（视黄醇）首先以视黄酯（RE）的形式储存在组织中，通过水解和受控的氧化代谢产生生物活性类维生素A，包括视黄酸（RA）。视黄酸是细胞分化的关键调节剂。对于肺，RA对于正常的出生后肺泡发育和成熟至关重要。RA是唯一一种能诱导肺泡隔形成的小分子，而肺泡隔形成是完全呼吸能力发展所必需的。RA还在成人肺气肿疾病模型和手术后组织再生中显示出治疗益处。我们的中心假设是：一种营养代谢物组合，VARA，由维生素A和它的类维生素A代谢物全反式RA组成，将协同作用，促进新生儿肺部RE的形成。VARA诱导的RE形成可能建立有利于内源性类维生素A产生的条件，并促进肺泡重塑（分隔）。在目的1中，我们将通过以下检查来检验VARA协同增加肺中RE的假设：（1a）几种类维生素A与视黄醇协同作用的有效性;（1b）在RA存在下肺对乳糜微粒中所含的新吸收的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用VARA治疗的新生儿的肺中观察到的协同反应。在目标2中，我们将通过研究肺和肝中关键因子（LRAT，CYP 26 B1和DHRS 3，一种视网膜还原酶）的时间依赖性基因表达和定位来检查VARA治疗的功能结局。最后，在此目的中，还将测试VARA是否在糖皮质激素抑制的肺泡分隔的临床相关模型中改善肺成熟。这两个综合的目标将提供有关VARA促进细胞分化和器官成熟的潜力的新知识，并改善出生后肺发育受损。公共卫生相关性：维生素A和视黄酸的组合，VARA，通过其增加肺中稳定的视黄酯库的能力，可以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、治疗生命后期肺损伤以及潜在癌症化学预防的临床潜力。通过揭示维生素A，RA和VARA对动物模型中肺部基因和酶的分子效应，这项研究将确定VARA是否需要进一步的临床前试验作为慢性肺病高危新生儿的治疗，以及成人肺损伤或化学预防的修复。

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.