The asymmetric cleavage of beta-carotene in mammalian embryonic development
哺乳动物胚胎发育中β-胡萝卜素的不对称裂解
基本信息
- 批准号:9181429
- 负责人:
- 金额:$ 31.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-01-01 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlcoholsAldehydesAll-Trans-RetinolBeta CaroteneBindingBinding SitesC10CarotenoidsCell LineCell RespirationCell SurvivalChildChild DevelopmentCitric Acid CycleCleaved cellCongenital AbnormalityDataDeveloping CountriesDevelopmentDietDoseEmbryoEmbryonic DevelopmentEnzymesExperimental Animal ModelExperimental ModelsFemaleFemale of child bearing ageFetal DeathFetusFibroblastsGenesGenetic TranscriptionGeographic LocationsGrowth and Development functionHealthHomeostasisHumanIn VitroIntakeInterventionKnock-outKnockout MiceLigandsLinkMalnutritionMetabolismMitochondriaModelingMorphologyMothersMouse ProteinMusMutant Strains MiceMutationNutrientNutritional statusOutputOxidation-ReductionOxidative PhosphorylationOxidative StressOxidesOxygenasesPathway interactionsPhenotypePhosphotransferasesPhysiologyPlayPopulationPregnancyPregnant WomenProductionProtein IsoformsProteinsPublic HealthPyruvate Dehydrogenase ComplexReactionReagentRegulationRespirationRetinaldehydeRetinoidsRetinol Binding ProteinsRoleSignal TransductionSourceSupplementationTestingTissuesToxic effectTretinoinVitamin AVitamin A DeficiencyVitamin B ComplexWomanWorkWorld Health Organizationapocarotenalbasein vivoinnovationmouse modelnovelpreventprogramspublic health relevance
项目摘要
DESCRIPTION (provided by applicant): Vitamin A is required for proper mammalian embryonic development, owing to defective transcriptional action of retinoic acid (RA), its active form. Deficient or excessive maternal vitamin A intake of this essential nutrient results in congenital abnormalities or fetal death in experimental animal models and humans. Notably, vitamin A deficiency (VAD) is the third most prevalent nutritional deficiency, and is an overwhelming public health issue, affecting hundreds of millions of people (predominantly women and children) in developing countries. The majority of the world population, especially in the above-mentioned geographic areas, relies on the vitamin A precursor β-carotene (BC) as a source of retinoids (vitamin A and its derivatives). In the embryo, BC obtained from the maternal diet can significantly contribute to the retinoid needs of the developing tissues upon conversion to retinaldehyde via the symmetric BC cleavage enzyme β,β-carotene-15,15'-oxygenase, CMO1. Retinaldehyde is then oxidized to retinoic acid, the master regulator of many genes that are crucial to embryogenesis. BC is also cleaved asymmetrically by β,β-carotene-9',10'-oxygenase, CMO2, generating C10 β-apocarotenal (C10 apoAL). While retinaldehyde could also be generated from C10 apoAL, the role of CMO2 and its reaction product during mammalian embryonic development is unknown. Our preliminary data indicate that the well-known detrimental effects of VAD on mouse embryogenesis are aggravated when CMO2 is inactive and BC is administered to the dams, despite expression of CMO1. We showed that the embryonic phenotype of mice lacking CMO2 on the retinol-binding protein (RBP) knockout background, an established model of VAD, was due to the low levels of C10 apoAL along with limited availability of retinoids. Supplementing CMO2-/-RBP-/- mice on a vitamin A deficient diet with C10 apoAL reduced congenital malformations. We propose that C10 apoAL serves as a ligand for PKCδ. This mitochondria-localized PKC isoform signals to the pyruvate dehydrogenase complex (PDHC), increasing its activity, with the purpose of coordinating the fuel flux to the citric acid cycle with the demands for ATP production. PKCδ is activated by redox
mechanisms, with a mandatory catalytic role of vitamin A (retinol) that binds the activation domains of the kinase. CMO2 localizes to mitochondria and C10 aopAL is structurally similar to retinol. We showed that C10 apoAL interacts with the retinol-binding domain of PKCδ and modulates respiration in mouse embryonic fibroblasts, in a PKCδ-dependent manner. Overall, our data suggest that disruption of PKC signaling and mitochondrial functions when C10 apoAL and vitamin A are limiting could be the underlying cause of the exacerbated phenotypes of mice lacking CMO2 in the presence of BC. With this application we seek to further understand the function of CMO2 and the mechanisms of C10 apoAL action during mammalian embryogenesis. Specifically, we will test whether C10 apoAL is essential for embryonic survival under conditions of VAD (Aim 1) and we will define the interaction between CMO2/β- apocarotenoids and PKCδ signaling network during embryonic development (Aim 2), both in vitro and ex vivo (Aim 2A) and in vivo (Aim 2B). Unique reagents, such as pure synthetic β-apocarotenoid compounds, and new mouse models, with inactivation of the PKCδ and carotenoid metabolism pathways, will be used to address the above-mentioned questions. Understanding the role of CMO2/β-apocarotenoids in embryogenesis is relevant to human health, as it will lead to novel interventions to ameliorate VAD-associated congenital defects.
描述(申请人提供):维生素A是哺乳动物胚胎正常发育所必需的,因为其活性形式维甲酸(RA)的转录作用有缺陷。在实验动物模型和人类中,母亲维生素A摄入不足或过多会导致先天畸形或胎儿死亡。值得注意的是,维生素A缺乏症是第三大最普遍的营养缺乏症,是一个压倒性的公共卫生问题,影响着发展中国家数以亿计的人(主要是妇女和儿童)。世界上大多数人口,特别是上述地理区域的人口,依赖维生素A前体β-胡萝卜素(BC)作为维甲酸(维生素A及其衍生物)的来源。在胚胎中,从母体饮食中获得的BC可以通过对称的BC裂解酶β,β-胡萝卜素-15,15‘-加氧酶CMo 1转化为视黄醛,从而显著促进发育组织对维甲酸的需求。然后,视黄醛被氧化成维甲酸,维甲酸是许多对胚胎发育至关重要的基因的主要调节者。BC也被β,β-胡萝卜素-9‘,10’-加氧酶Cmo2不对称切割,产生C10载脂蛋白AL(C10apoAL)。虽然C10载脂蛋白AL也可以产生视黄醛,但CMO2及其反应产物在哺乳动物胚胎发育中的作用尚不清楚。我们的初步数据表明,众所周知的VAD对小鼠胚胎发育的不利影响在CMO2处于非活性状态时加剧,并且尽管CMO1表达,但仍给DAMS注射BC。我们发现,在视黄醇结合蛋白(RBP)基因敲除背景上缺乏CMO2的小鼠的胚胎表型是由于低水平的C10 apoAL和有限的维甲酸可获得性所致。在缺乏维生素A的饮食中给CMO2-/-RBP-/-小鼠补充C10载脂蛋白可减少先天畸形。我们建议将C10apoAL作为PKCδ的配体。这种线粒体定位的PKC亚型向丙酮酸脱氢酶复合体(PDHC)发出信号,增加其活性,目的是协调柠檬酸循环的燃料流量和ATP生产的需求。PKcδ被氧化还原激活
机制,与维生素A(视黄醇)的强制催化作用,结合的激活域的激酶。CMO2定位于线粒体,而C10aopAL在结构上与视黄醇相似。我们发现,C10apoAL与蛋白激酶Cδ的视黄醇结合区相互作用,并以蛋白激酶Cδ依赖的方式调节小鼠胚胎成纤维细胞的呼吸。总体而言,我们的数据表明,当C10载脂蛋白A和维生素A受限时,PKC信号和线粒体功能的中断可能是在BC存在下缺乏CMO2的小鼠表型恶化的潜在原因。通过这一应用,我们试图进一步了解CMO2在哺乳动物胚胎发育过程中的功能和C10apoAL的作用机制。具体地说,我们将测试C10载脂蛋白AL是否对VAD条件下的胚胎存活是必要的(AIM 1),我们将定义Cmo2/β-apcaratin类化合物与胚胎发育过程中的PKCδ信号网络的相互作用(Aim 2),包括体外和体外(Aim 2A)和体内(Aim 2B)。将使用独特的试剂,如纯合成的β-阿帕类胡萝卜素化合物,以及具有PKCδ和类胡萝卜素代谢途径失活的新小鼠模型来解决上述问题。了解cmo2/β-载脂类胡萝卜素在胚胎发育中的作用与人类健康有关,因为它将导致新的干预措施来改善与维生素D相关的先天性缺陷。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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{{ truncateString('Loredana Quadro', 18)}}的其他基金
The asymmetric cleavage of beta-carotene in mammalian embryonic development
哺乳动物胚胎发育中β-胡萝卜素的不对称裂解
- 批准号:
9029615 - 财政年份:2016
- 资助金额:
$ 31.57万 - 项目类别:
The role of b-carotene in maternal-fetal nutrition
β-胡萝卜素在母婴营养中的作用
- 批准号:
7933182 - 财政年份:2009
- 资助金额:
$ 31.57万 - 项目类别:
The role of b-carotene in maternal-fetal nutrition
β-胡萝卜素在母婴营养中的作用
- 批准号:
7568995 - 财政年份:2008
- 资助金额:
$ 31.57万 - 项目类别:
The role of b-carotene in maternal-fetal nutrition
β-胡萝卜素在母婴营养中的作用
- 批准号:
8265875 - 财政年份:2008
- 资助金额:
$ 31.57万 - 项目类别:
The role of b-carotene in maternal-fetal nutrition
β-胡萝卜素在母婴营养中的作用
- 批准号:
7349948 - 财政年份:2008
- 资助金额:
$ 31.57万 - 项目类别:
The role of b-carotene in maternal-fetal nutrition
β-胡萝卜素在母婴营养中的作用
- 批准号:
7764758 - 财政年份:2008
- 资助金额:
$ 31.57万 - 项目类别:
The role of b-carotene in maternal-fetal nutrition
β-胡萝卜素在母婴营养中的作用
- 批准号:
8737793 - 财政年份:2008
- 资助金额:
$ 31.57万 - 项目类别:
The role of b-carotene in maternal-fetal nutrition
β-胡萝卜素在母婴营养中的作用
- 批准号:
8042693 - 财政年份:2008
- 资助金额:
$ 31.57万 - 项目类别:
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