Molecular Regulation of LRAT and CYP26 in Lung and Liver

肺和肝中 LRAT 和 CYP26 的分子调控

• 批准号: 7614282
• 负责人: A. CATHARINE ROSS
• 金额: $ 28.21万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614282
• 关键词: Activities of Daily Living; Address; Adrenal Cortex Hormones; Adult; All-Trans-Retinol; Alveolar; Animal Model; Attenuated; Biological; Bronchopulmonary Dysplasia; CYP26B1 gene; Cell Differentiation process; Cell Proliferation Regulation; Cell Respiration; Chemoprevention; Chronic lung disease; Chylomicrons; Clinical; Collagen Fiber; Complex; Cytochrome P450; Development; Diet; Disease; Effectiveness; Elastin; Embryonic Development; Enzyme Gene; Enzymes; Esters; Family; Fibroblasts; Figs - dietary; Gene Expression; Genes; Glucocorticoids; Grant; Growth; Health; Homeostasis; Hormones; Hydrolysis; In Situ Hybridization; Inflammation; Knowledge; Life; Ligands; Liver; Lung; Lung diseases; Maintenance; Metabolism; Methods; Microarray Analysis; Modeling; Molecular; Neonatal; Newborn Infant; Nuclear Hormone Receptors; Nutrient; Operative Surgical Procedures; Organ; Organism; Outcome; Oxidoreductase; Pattern; Physiological; Play; Preclinical Testing; Production; Property; Rattus; Regulation; Research; Research Project Grants; Retinal; Retinoids; Retinol Metabolism Pathway; Role; Series; Sum; Supplementation; Testing; Therapeutic; Therapeutic Agents; Time; Time Study; Tissue Stains; Tissues; Tretinoin; Vitamin A; Work; analog; cancer chemoprevention; clinically relevant; density; functional outcomes; high risk; improved; lecithin-retinol acyltransferase; lung development; lung injury; lung maturation; lung volume; neonate; postnatal; prevent; public health relevance; repaired; respiratory; response; small molecule; tissue regeneration; uptake

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.

描述（由申请人提供）：饮食衍生的维生素A（视黄醇）首先以视网膜酯（RE）的形式存储在组织中，通过水解和受控的氧化代谢产生了生物活性类视黄素，包括视黄酸（RA）。视黄酸是细胞分化的关键调节剂。对于肺部，RA对于正常的产后肺泡发育和成熟至关重要。 RA是唯一显示出诱导肺肺泡分离（间隔出生）的小分子，这是发展全呼吸能力所必需的。 RA还显示出在术后成人肺部肿瘤疾病和组织再生模型中的治疗益处。我们的中心假设是：由维生素A及其类似激素的代谢产物全反射剂组成的营养量代谢物组合，将协同作用，以促进新生儿肺中的重新形成。 VARA诱导的重新形成可能会建立有益于内源性类维生素的有益的条件，并促进肺泡重塑（分隔）。在AIM 1中，我们将测试以下假设，即通过检查：（1A）几类维生素类似于视黄醇协同作用，可以协同增加肺中的RE； （1b）在RA存在的情况下，乳糖中包含的新吸收的VA的肺摄取是否增加； （1C）炎症是肺动不成熟的伴随因子，会改变或减弱我们在用VARA治疗的新生儿肺中观察到的协同反应。在AIM 2中，我们将通过研究时间依赖性基因表达和关键因素的定位（LRAT，CYP26B1和DHRS3，一种视网膜还原酶）的定位来检查VARA处理的功能结果。最后，在此目标中还将测试VARA在糖皮质激素抑制的肺泡分离的临床相关模型中是否改善了肺部成熟。这两个综合目的将提供有关VARA促进细胞分化和器官成熟的潜力的新知识，并改善产后肺发育受损。公共卫生相关性：通过增加肺中稳定的视黄酯池的能力，维生素A和视黄酸的结合可能建立有利于肺部成熟和修复的疾病。因此，VARA似乎具有预防新生儿支气管肺发育不良的临床潜力，在生命后期治疗肺损伤，并可能用于癌症化学预防。通过揭示动物模型中肺中维生素A，RA和VARA对肺中基因和酶的分子作用，该研究将确定VARA是否需要进一步的临床前测试作为针对慢性肺部疾病高风险的新生儿的疗法，以及成人修复肺损伤或化学的疗法。