Mechanisms of regulation of retinoic acid homeostasis

视黄酸稳态的调节机制

基本信息

批准号：
8764616
负责人：
Nina Isoherranen
金额：
$ 29.98万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764616
关键词：
Adult Adverse effects Affect Alzheimer&apos s Disease B-Lymphocytes Bile Acids Binding Proteins Biochemical Biochemical Process Biological Biological Process CYP26B1 gene Cell Cycle Cell Cycle Regulation Cells Cessation of life Childhood Chordata Competence Coupled Cytochrome P450 Development Diet Disease Disease Progression Drug Kinetics Drug Targeting Embryonic and Fetal Development Enzyme Kinetics Enzyme Tests Enzymes Epithelial Epithelium Foundations Future Gene Expression Regulation Generations Genetic Polymorphism Genetic Processes Germ Cells Glucose Goals Growth Health Hepatocyte Hereditary Disease Histocompatibility Testing Homeostasis Human Ichthyoses Immune In Vitro Individual Islets of Langerhans Kidney Kidney Diseases Kinetics Knock-out Knockout Mice Knowledge Lead Life Lipids Liver Lung Maintenance Mass Spectrum Analysis Measures Mediating Metabolism Methods Modeling Mus Neurodegenerative Disorders Organ Overdose Pancreas Pharmaceutical Preparations Pharmacology Phenotype Physiological Physiology Play Process Psoriasis Public Health Pulmonary alveolar structure Regulation Reproduction Retinoids Role Signal Transduction Signaling Molecule System Testing Tissue Differentiation Tissue Sample Tissues Toxic Environmental Substances Toxic effect Tretinoin Vitamin A Weight Gain Whole Organism Work Xenobiotics adverse outcome aldehyde dehydrogenases base blood glucose regulation cell type cellular retinoic acid binding protein direct application enzyme activity glucose metabolism improved in vivo inhibitor/antagonist lipid metabolism novel novel therapeutic intervention pharmacokinetic model podocyte protein protein interaction public health relevance research study retinoic acid 4-hydroxylase skin disorder therapy development tissue repair tool trafficking

项目摘要

DESCRIPTION (provided by applicant): All-trans-retinoic acid (atRA), the biologically active metabolite of dietary Vitamin A, is essential for mediating diverse biological functions in multipl tissues such as the liver, kidney, lung and pancreas. The different biological actions of atRA are regulated through tissue concentration gradients of atRA, but there are considerable gaps in our knowledge on how the tissue specific signaling of atRA is regulated during childhood and adult life. We propose that atRA concentration gradients are generated by regulated expression and activity of the enzymes synthesizing atRA (ALDH1As), those that metabolize atRA (CYP26s) and cellular retinoic acid binding proteins (CRABPs). Our central hypothesis is that alterations in the activity or expression of these enzymes change atRA signaling and distribution, contribute to disease development in specific tissues and result in adverse effects. To test this hypothesis we will first characterize atRA metabolism in cell systems and establish the role of cellular retinoic acid binding proteins (CRABPs) in modulating atRA clearance, signaling and distribution. We will use basic biochemical and enzyme kinetic methods and in vitro cell experiments to establish the role and kinetics of direct protein-protein interactions between CYP26s and CRABPs. We will then establish the tissue and cell type specific roles of ALDH1A, CYP26 and CRABP enzymes in maintaining atRA homeostasis in humans and mice. This will be done using normal human and mouse tissues, novel high sensitivity mass spectrometry methods, generating new conditional knock-out mice of CYP26 enzymes, testing pharmacological effects of CYP26 and ALDH1A inhibitors and using physiologically based pharmacokinetic (PBPK) modeling. To determine the overall physiological importance of these enzymatic processes, we will use the knock-out mice and our pharmacological tools in vitro and in vivo, to demonstrate that altered CYP26 or ALDH1A activity impairs normal physiological atRA signaling in target tissues. We will focus on atRA signaling in the liver, kidney, pancreas and lung due to the existing knowledge that atRA signaling plays a fundamental role in these tissues. Together these studies will generate a new and unique integrative model of retinoid homeostasis that will be useful in evaluating and predicting the effects of xenobiotics, new therapeutic approaches, disease processes and genetic factors in altering tissue retinoid signaling. This will have major impact in improving human health as it has direct application in improving our understanding of the processes involved in lipid and glucose homeostasis in the liver and the pancreas, in development and treatment of nephropathies and in lung alveoli health. In addition, the knowledge gained through these studies will improve our understanding of the role of atRA signaling during childhood development and maturation, and can be extended to improve our understanding of the role of atRA in skin diseases such as psoriasis and ichthyosis and in neurodegenerative diseases such as Alzheimer's and dementia in which atRA signaling has been shown to be altered.

描述（由申请人提供）：全反式视黄酸 (atRA) 是膳食维生素 A 的生物活性代谢物，对于介导肝脏、肾脏、肺和胰腺等多种组织中的多种生物功能至关重要。 atRA 的不同生物学作用是通过 atRA 的组织浓度梯度来调节的，但我们对于 atRA 的组织特异性信号在儿童和成年期间如何受到调节的知识存在相当大的空白。我们认为 atRA 浓度梯度是通过合成 atRA (ALDH1As) 的酶、代谢 atRA (CYP26s) 和细胞视黄酸结合蛋白 (CRABP) 的酶的表达和活性的调节而产生的。我们的中心假设是这些酶的活性或表达会改变 atRA 信号传导和分布，导致特定组织中疾病的发展并导致不良影响。为了验证这一假设，我们将首先表征细胞系统中的 atRA 代谢并确定细胞视黄酸的作用酸结合蛋白 (CRABP) 调节 atRA 清除、信号传导和分布。我们将使用基本的生化和酶动力学方法以及体外细胞实验来建立 CYP26 和 CRABP 之间直接蛋白质-蛋白质相互作用的作用和动力学。然后，我们将确定 ALDH1A、CYP26 和 CRABP 酶在维持人类和小鼠 atRA 稳态中的组织和细胞类型特异性作用。这将使用正常人类和小鼠组织、新型高灵敏度质谱方法、生成新的 CYP26 酶条件敲除小鼠、测试 CYP26 和 ALDH1A 抑制剂的药理作用以及使用基于生理学的药代动力学 (PBPK) 模型来完成。为了确定这些酶促过程的整体生理重要性，我们将在体外和体内使用敲除小鼠和我们的药理学工具来证明改变的 CYP26 或 ALDH1A 活性会损害靶组织中正常的生理 atRA 信号传导。我们将重点关注肝脏、肾脏、胰腺和肺中的 atRA 信号传导，因为现有的知识表明 atRA 信号传导在这些组织中发挥着重要作用。这些研究将共同产生一种新的、独特的类维生素A稳态综合模型，该模型将有助于评估和预测异生素、新治疗方法、疾病过程和改变组织类维生素A信号传导的遗传因素的影响。这将产生重大影响改善人类健康，因为它可直接应用于提高我们对肝脏和胰腺中脂质和葡萄糖稳态过程的理解、肾病的发展和治疗以及肺泡健康。此外，通过这些研究获得的知识将提高我们对 atRA 信号在儿童发育和成熟过程中的作用的理解，并可以扩展以提高我们对 atRA 在牛皮癣和鱼鳞病等皮肤病以及神经退行性疾病中的作用的理解例如阿尔茨海默病和痴呆症，其中 atRA 信号传导已被证明发生了改变。