Regulatory Mechanisms of Renal Vitamin D Activation and Degradation
肾脏维生素 D 激活和降解的调节机制
基本信息
- 批准号:10373006
- 负责人:
- 金额:$ 39.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-11 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:BloodBone DiseasesCRISPR/Cas technologyCYP27B1 geneCellsChIP-seqChemicalsChronic Kidney FailureComplexDihydroxycholecalciferolsDiseaseDistalEndocrineEnhancersExperimental ModelsGene ExpressionGenesGenetic TranscriptionGenomic SegmentGenomicsHomeostasisHormonalHormonesHumanIndividualInflammatoryIntestinesIntronsKidneyLocationMaintenanceMediatingMedicineMetabolic ActivationMetabolismMethodsMineralsModelingModificationMolecularMouse StrainsMusMutation AnalysisNaturePhenotypePhysiologicalPlayProductionPropertyRegulationRenal functionResearchRoleSignal TransductionSiteSkeletonSystemTestingTissuesVitamin Dcell typecombatdesigndietarydietary manipulationgenomic locushormone regulationin vivonovelnovel strategiespromoterresponseselective expressiontranscription factorvirtual
项目摘要
PROJECT SUMMARY/ABSTRACT
1,25-Dihydroxyvitamin D (1,25(OH)2D3) is synthesized in the kidney by Cyp27b1 and inactivated in all target
tissues via Cyp24a1. The two genes are reciprocally regulated in the kidney by a number of hormones that
serve to maintain appropriate physiologic levels of circulating 1,25(OH)2D3. In spite of their importance,
however, little is known of the molecular details that facilitate expression of Cyp27b1 in the kidney or of
Cyp24a1 in this tissue and elsewhere. This represents an enormous deficit in our understanding of the vitamin
D system, a gap that is highlighted in a variety of diseases of mineral metabolism. In recent studies, we have
identified key genomic regions in the Cyp27b1 locus in mice that mediate Cyp27b1 regulation by PTH, FGF23
and 1,25(OH)2D3, a module that is present only in the kidney. Deletion of components of this module reduce
Cyp27b1 expression in the kidney but have no effect on Cyp27b1 expression in non-renal target cells
(NRTCs). In view of these findings, we propose the following molecular studies. Aim 1: Characterize the
endocrine module and its individual components in the mouse kidney that mediates Cyp27b1
expression and regulation by PTH, 1,25(OH)2D3 and FGF23 in vivo. We will use ChIP-seq analysis and
CRISPR/Cas9 deletion studies in vivo to further characterize a regulatory module we have discovered in the
kidney that functions to regulate the expression of Cyp27b1. We will also define the location of an independent
module in the Cyp27b1 gene locus that mediates the actions of inflammatory signaling in NRTCs. These
studies are designed to advance our understanding of the molecular mechanisms that underpin the metabolic
activation of vitamin D. Aim 2: Characterize the regulatory sub-modules that control Cyp24a1 expression
and regulation by PTH, 1,25(OH)2D3 and FGF23 in the kidney in vivo. Cyp24a1 in the kidney plays a
coordinating role in regulating blood levels of 1,25(OH)2D3 and other vitamin D metabolites. We will use the
methods outlined in Aim 1 to elucidate the genomic mechanisms through which this gene is downregulated by
PTH and upregulated by both FGF23 and 1,25(OH)2D3. Mutational analysis in mice will allow us to define the
clusters of enhancers and the sites of action of transcription factors and comodulators that are responsible for
these activities. Aim 3: Utilize dietary manipulation to test and confirm regulatory hypotheses developed
in Cyp27b1-compromised mouse strains relevant to disease. In this aim, we plan to test a hypothetical
model that explains the complex phenotypes that have emerged following deletion of components of the
kidney-specific regulatory module. We will use dietary manipulation of Ca, Pi, and vitamin D metabolites to test
our hypotheses.
项目概要/摘要
1,25-二羟基维生素 D (1,25(OH)2D3) 在肾脏中由 Cyp27b1 合成,并在所有目标中失活
通过 Cyp24a1 的组织。这两个基因在肾脏中受到多种激素的相互调节,
用于维持循环 1,25(OH)2D3 的适当生理水平。尽管它们很重要,
然而,我们对促进 Cyp27b1 在肾脏或细胞中表达的分子细节知之甚少。
该组织和其他地方的 Cyp24a1。这表明我们对维生素的理解存在巨大缺陷
D系统的缺口在多种矿物质代谢疾病中凸显。在最近的研究中,我们有
确定了小鼠 Cyp27b1 基因座中通过 PTH、FGF23 介导 Cyp27b1 调节的关键基因组区域
1,25(OH)2D3,一种仅存在于肾脏中的模块。删除该模块的组件reduce
Cyp27b1 在肾脏中表达,但对非肾脏靶细胞中 Cyp27b1 表达没有影响
(NRTC)。鉴于这些发现,我们提出以下分子研究。目标 1:表征
小鼠肾脏中介导 Cyp27b1 的内分泌模块及其各个成分
PTH、1,25(OH)2D3 和 FGF23 在体内的表达和调节。我们将使用 ChIP-seq 分析
体内 CRISPR/Cas9 缺失研究进一步表征了我们在
肾的功能是调节 Cyp27b1 的表达。我们还将定义一个独立的位置
Cyp27b1 基因位点中介导 NRTC 炎症信号传导作用的模块。这些
研究旨在增进我们对代谢基础分子机制的理解
维生素 D 的激活。目标 2:表征控制 Cyp24a1 表达的调节子模块
以及体内肾脏中 PTH、1,25(OH)2D3 和 FGF23 的调节。 Cyp24a1 在肾脏中发挥着
在调节 1,25(OH)2D3 和其他维生素 D 代谢物的血液水平中发挥协调作用。我们将使用
目标 1 中概述的方法阐明了该基因被下调的基因组机制
PTH 并受 FGF23 和 1,25(OH)2D3 的上调。小鼠的突变分析将使我们能够定义
增强子簇以及负责转录因子和共调节子的作用位点
这些活动。目标 3:利用饮食控制来测试和确认所制定的监管假设
在与疾病相关的 Cyp27b1 受损小鼠品系中。为了这个目标,我们计划测试一个假设的
该模型解释了删除组件后出现的复杂表型
肾脏特异性调节模块。我们将使用钙、磷和维生素 D 代谢物的饮食控制来测试
我们的假设。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Genomic Mechanisms Governing Mineral Homeostasis and the Regulation and Maintenance of Vitamin D Metabolism.
- DOI:10.1002/jbm4.10433
- 发表时间:2021-01
- 期刊:
- 影响因子:3.8
- 作者:Pike JW;Lee SM;Benkusky NA;Meyer MB
- 通讯作者:Meyer MB
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{{ truncateString('J WESLEY PIKE', 18)}}的其他基金
Transcriptional Control of Mouse FGF23 Expression in Health and Disease
健康和疾病中小鼠 FGF23 表达的转录控制
- 批准号:
9904622 - 财政年份:2019
- 资助金额:
$ 39.27万 - 项目类别:
Regulatory Mechanisms of Renal Vitamin D Activation and Degradation
肾脏维生素 D 激活和降解的调节机制
- 批准号:
9888365 - 财政年份:2018
- 资助金额:
$ 39.27万 - 项目类别:
Integrative genomics to define osteocyte differentiation, regulation and function
综合基因组学定义骨细胞分化、调节和功能
- 批准号:
8691297 - 财政年份:2014
- 资助金额:
$ 39.27万 - 项目类别:
Integrative genomics to define osteocyte differentiation, regulation and function
综合基因组学定义骨细胞分化、调节和功能
- 批准号:
8909062 - 财政年份:2014
- 资助金额:
$ 39.27万 - 项目类别:
Molecular Mechanisms of RANKL Activation in Osteoblasts
成骨细胞中 RANKL 激活的分子机制
- 批准号:
7989031 - 财政年份:2009
- 资助金额:
$ 39.27万 - 项目类别:
Vitamin D Ligands and Regulation of Calcium Homeostasis
维生素 D 配体和钙稳态调节
- 批准号:
7461164 - 财政年份:2008
- 资助金额:
$ 39.27万 - 项目类别:
Vitamin D Ligands and Regulation of Calcium Homeostasis
维生素 D 配体和钙稳态调节
- 批准号:
7591143 - 财政年份:2008
- 资助金额:
$ 39.27万 - 项目类别:
Vitamin D Ligands and Regulation of Calcium Homeostasis
维生素 D 配体和钙稳态调节
- 批准号:
8054311 - 财政年份:2008
- 资助金额:
$ 39.27万 - 项目类别:
Vitamin D Ligands and Regulation of Calcium Homeostasis
维生素 D 配体和钙稳态调节
- 批准号:
8237042 - 财政年份:2008
- 资助金额:
$ 39.27万 - 项目类别:
Molecular Mechanisms of Rankl Activation In Osteoblasts
成骨细胞Rankl激活的分子机制
- 批准号:
8536514 - 财政年份:2007
- 资助金额:
$ 39.27万 - 项目类别:
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