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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）：全反式维甲酸（atRA）是膳食维生素A的生物活性代谢物，对于介导肝、肾、肺和胰腺等多种组织的多种生物功能至关重要。atRA的不同生物学作用是通过atRA的组织浓度梯度调节的，但我们对atRA的组织特异性信号是如何在儿童和成人生活中调节的了解还存在相当大的空白。我们认为atRA浓度梯度是由合成atRA的酶（ALDH1As）、代谢atRA的酶（CYP26s）和细胞维甲酸结合蛋白（CRABPs）的表达和活性调控产生的。我们的中心假设是