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Molecular Regulation of LRAT and CYP26 in Lung and Liver

肺和肝中 LRAT 和 CYP26 的分子调控

基本信息

批准号：
8250390
负责人：
A. CATHARINE ROSS
金额：
$ 27.32万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250390
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 repair lung volume neonate postnatal prevent repaired respiratory response small molecule tissue regeneration uptake

项目摘要

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）首先以视黄醇酯（RE）的形式储存在组织中，通过水解和受控的氧化代谢生成生物活性类维生素A，包括视黄酸（RA）。视黄酸是细胞分化的关键调节剂。对于肺部来说，RA对正常的产后肺泡发育和成熟至关重要。RA是唯一能诱导肺泡分隔的小分子，而肺泡分隔是发育完全呼吸能力所必需的。RA在成人肺气肿疾病和术后组织再生模型中也显示出治疗益处。我们的中心假设是：一种营养代谢物组合，VARA，由维生素A及其激素样代谢物all-trans-RA组成，将协同作用促进新生儿肺部RE的形成。vara诱导的RE形成可能为内源性类维生素a生成创造有利条件，并促进肺泡重塑（分隔）。在Aim 1中，我们将通过以下检查来检验VARA协同增加肺部RE的假设：（1a）几种类维生素a与视黄醇协同的有效性；（1b）在类风湿性关节炎存在时，肺对乳糜微粒中新吸收的VA的吸收是否增加；（1c）炎症（肺不成熟的伴随因素）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Aim 2中，我们将通过研究肺和肝脏中关键因子（LRAT， CYP26B1和DHRS3，一种视网膜还原酶）的时间依赖性基因表达和定位来检查VARA治疗的功能结果。最后，本研究还将在糖皮质激素抑制肺泡分隔的临床相关模型中测试VARA是否能促进肺成熟。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和视黄酸（VARA）的结合，通过其在肺中增加稳定的视黄酯库的能力，可能建立有利于肺成熟和修复的条件。因此，VARA似乎在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的癌症化学预防方面具有临床潜力。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效应，本研究将确定VARA是否值得进一步的临床前试验，以作为慢性肺病高风险新生儿的治疗方法，以及用于成人肺损伤修复或化学预防。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An Atherogenic Diet Disturbs Aquaporin 5 Expression in Liver and Adipocyte Tissues of Apolipoprotein E-Deficient Mice: New Insights into an Old Model of Experimental Atherosclerosis.

DOI：
10.3390/biomedicines9020150
发表时间：
2021-02-04
期刊：
Biomedicines
影响因子：
4.7
作者：
da Silva IV;Whalen CA;Mattie FJ;Florindo C;Huang NK;Heil SG;Neuberger T;Ross AC;Soveral G;Castro R
通讯作者：
Castro R

Shifts in dietary carbohydrate-lipid exposure regulate expression of the non-alcoholic fatty liver disease-associated gene PNPLA3/adiponutrin in mouse liver and HepG2 human liver cells.

DOI：
10.1016/j.metabol.2014.06.016
发表时间：
2014-10
期刊：
METABOLISM-CLINICAL AND EXPERIMENTAL
影响因子：
9.8
作者：
Hao, Lei;Ito, Kyoko;Huang, Kuan-Hsun;Sae-tan, Sudathip;Lambert, Joshua D.;Ross, A. Catharine
通讯作者：
Ross, A. Catharine

Retinol combined with retinoic acid increases retinol uptake and esterification in the lungs of young adult rats when delivered by the intramuscular as well as oral routes.

当通过肌内和口服途径递送时，视黄醇与视黄酸结合可增加年轻成年大鼠肺部的视黄醇摄取和酯化作用。