Role Of Retinoid Oxidoreductase Complex In Controlling The Embryonic Development

类维生素A氧化还原酶复合物在控制胚胎发育中的作用

• 批准号: 10658252
• 负责人: Olga V Beliaeva
• 金额: $ 31.19万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658252
• 关键词: Address; All-Trans-Retinol; Anabolism; Attenuated; Automobile Driving; Back; Binding; Buffers; Cells; Complex; Cytoplasm; Data; Defect; Development; Developmental Process; Dietary intake; Disease; Ectopic Expression; Embryo; Embryonic Development; Ensure; Environment; Enzymatic Biochemistry; Enzymes; Epigenetic Process; Etiology; Exercise; Fertilization; Fluorescence Resonance Energy Transfer; Foundations; Future; Generations; Genes; Genetic Transcription; Homeobox Genes; Homeostasis; Human; In Vitro; Individual; Knock-in; Ligands; Modeling; Monitor; Mutation; NADH; NADP; Nuclear; Orthologous Gene; Output; Oxidoreductase; Pathway interactions; Pattern; Physiological; Process; Property; Proteins; Publishing; Recycling; Regulation; Retinaldehyde; Retinoic Acid Binding; Retinoic Acid Receptor; Retinoids; Retinol dehydrogenase; Role; Signal Transduction; Testing; Tretinoin; Visualization; Vitamin A; Work; Zebrafish; Zebrafish Proteins; animal tissue; genome editing; in vivo; knockout gene; malformation; mosaic; novel; oxidation; prevent; progenitor; receptor; response; self-renewal; sensor; small molecule; spatiotemporal; transcription factor

ABSTRACT All-trans-retinoic acid (RA) is the main physiologically active derivative of vitamin A, which serves as a ligand for nuclear transcription factors, RA receptors. During development, RA is produced in a quickly changing spatiotemporal pattern to control the expression of precise sets of genes at different developmental stages. Critical RA-sensitive processes during development are RA-concentration dependent, which underscores the importance of the precise control over RA synthesis in a strictly defined and rapidly regulated manner. Biosynthesis of RA includes reversible rate-limiting oxidation of retinol to all-trans-retinaldehyde, followed by irreversible oxidation of all-trans-retinaldehyde to RA. Multiple studies examined the roles of the enzymes catalyzing the oxidation of retinaldehyde and degradation of RA in establishing the dynamic pattern of RA concentration. However, the mechanism regulating the upstream rate-limiting step, which supplies the immediate RA precursor, retinaldehyde, in a precise spatiotemporal pattern remains unknown. It has been established that two proteins, retinol dehydrogenase 10 (RDH10) and short-chain dehydrogenase/reductase 3 (DHRS3), are critical for the control of retinaldehyde levels during development. We have recently discovered that DHRS3 binds to RDH10 and upon binding reduces the output of retinaldehyde by RDH10 by recycling retinaldehyde back to retinol. As a result, the formation of the bifunctional retinoid oxidoreductase complex (ROC) that consists of an oxidative RDH10 and reductive DHRS3 attenuates the RA biosynthesis. Whether this mechanism works in vivo and whether ROC exists in animal tissues is unknown, but if proven to be true, this finding will have a paradigm-shifting effect on our understanding of the mechanisms that regulate embryogenesis through vitamin A. The major hypothesis driving this proposal is that ROC represents a previously unrecognized universally conserved mechanism that can both provide the RA synthesis with robustness (Aim 1) and enable the dynamic changes in RA spatiotemporal pattern by regulating the levels of RA precursor (Aim 2). The hypothesis will be tested using a zebrafish embryogenesis model to take advantage of external fertilization and transparency of zebrafish for intra-vital visualization of RA synthesis and formation of the complex. Successful completion of these studies will advance the field at the conceptual level by demonstrating a mechanistically novel model of producing strictly controlled spatiotemporal gradients of small molecules. These findings will lay the foundation for a better understanding of the mechanisms of congenital diseases associated with dysregulation of RA homeostasis.

摘要 全反式维甲酸(RA)是维生素A的主要生理活性衍生物，作为一种配体 对于核转录因子，RA受体。在发展过程中，RA是在一个快速变化的环境中产生的 时空模式来控制不同发育阶段的精确基因集的表达。 发育过程中对RA敏感的关键过程依赖于RA浓度，这突显了 以严格定义和快速调节的方式精确控制RA合成的重要性。 维甲酸的生物合成包括可逆的限速氧化视黄醇为全反式视黄醛，然后是 全反式视黄醛不可逆氧化为RA。多项研究检验了这些酶的作用 视黄醛氧化和视黄酸降解在建立视黄醛动力学模式中的作用 集中精神。然而，调节上游限速步骤的机制提供了即时的 RA的前体，视黄醛，在精确的时空模式下仍然未知。已经确定， 视黄醇脱氢酶10(RDH10)和短链脱氢/还原酶3(DHRS3)是 在发育过程中对控制视黄醛水平至关重要。我们最近发现DHRS3 与RDH10结合并在结合时通过回收视黄醛来减少RDH10产生的视黄醛 回到视黄醇。结果，双功能维甲酸氧化还原酶复合体(ROC)的形成包括 氧化的RDH10和还原的DHRS3的作用减弱了RA的生物合成。这一机制是否有效 在活体中以及在动物组织中是否存在ROC尚不清楚，但如果被证明是真的，这一发现将具有 范式转换对我们理解通过维生素调节胚胎发生的机制的影响 答：推动这一提议的主要假设是，中华民国代表了一个以前没有得到普遍承认的 保守机制，既能为RA合成提供健壮性(目标1)，又能使动态 通过调节类风湿因子前体水平改变类风湿关节炎的时空模式(目标2)。假设将是 使用斑马鱼胚胎发生模型进行测试，以利用外部受精和透明 斑马鱼用于活体可视化RA的合成和形成复合体。 这些研究的成功完成将在概念层面上推进这一领域，因为它展示了 产生严格控制的小分子时空梯度的机械新模型。这些 这些发现将为更好地理解与先天性疾病相关的机制奠定基础。 RA动态平衡失调。