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: 8099766
• 负责人: A. CATHARINE ROSS
• 金额: $ 27.34万
• 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/8099766
• 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; Chromosome Mapping; Chronic lung disease; Chylomicrons; Clinical; Collagen Fiber; Complex; Cytochrome P450; Development; Diet; Disease; Effectiveness; Elastin Fiber; Embryonic Development; Enzyme Gene; Enzymes; Esters; Family; Fibroblasts; 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; 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; 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视黄醇，包括视黄酸（RA）。视黄酸是细胞分化的关键调节剂。对于肺部来说，RA 对于出生后肺泡的正常发育和成熟至关重要。 RA 是唯一被证明可诱导肺泡间隔（间隔生长）的小分子，这是发展完全呼吸能力所必需的。 RA 在成人肺气肿疾病模型和术后组织再生中也显示出治疗效果。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，促进新生儿肺部 RE 的形成。 VARA 诱导的 RE 形成可能会建立有利于内源性类视黄醇生成的条件，并促进肺泡重塑（隔膜）。在目标 1 中，我们将通过检查以下内容来检验 VARA 协同增加肺部 RE 的假设：(1a) 几种视黄醇与视黄醇协同作用的有效性； (1b) 在存在 RA 的情况下，肺部对乳糜微粒中新吸收的 VA 的摄取是否增加； (1c) 炎症（肺部不成熟的伴随因素）是否会改变或减弱我们在接受 VARA 治疗的新生儿肺部观察到的协同反应。在目标 2 中，我们将通过研究肺和肝脏中时间依赖性基因表达和关键因子（LRAT、CYP26B1 和 DHRS3（一种视网膜还原酶））的定位来检查 VARA 治疗的功能结果。最后，为此目的还将测试 VARA 是否可以在糖皮质激素抑制肺泡间隔的临床相关模型中改善肺成熟。这两个综合目标将提供关于 VARA 促进细胞分化和器官成熟以及改善出生后肺部发育受损的潜力的新知识。公共健康相关性：维生素 A 和视黄酸 VARA 的组合，通过其增加肺部稳定的视黄酯池的能力，可能会创造有利于肺部成熟和修复的条件。因此，VARA 似乎具有预防新生儿支气管肺发育不良、治疗晚年肺损伤以及癌症化学预防的临床潜力。通过在动物模型中揭示维生素 A、RA 和 VARA 对肺部基因和酶的分子影响，本研究将确定 VARA 是否值得进一步临床前测试作为慢性肺病高风险新生儿的治疗方法，以及成人肺损伤的修复或化学预防。