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

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.
项目总结/摘要 1,25-二羟基维生素D(1,25(OH)2D 3)在肾脏中由Cyp 27 b1合成,并在所有靶点中失活 通过Cyp 24 a1表达。这两种基因在肾脏中受到多种激素的调节, 用于维持循环1,25(OH)2D 3的适当生理水平。尽管它们很重要, 然而,对于促进Cyp 27 b1在肾脏中表达的分子细节或Cyp 27 b1在肾脏中表达的分子细节知之甚少。 CYP 24 A1在这个组织和其他地方。这代表了我们对维生素的理解存在巨大的缺陷 D系统,这是一个缺口,在各种疾病的矿物质代谢突出。在最近的研究中, 确定了小鼠Cyp 27 b1基因座中的关键基因组区域,其通过PTH、FGF 23介导Cyp 27 b1调节 和1,25(OH)2D 3,一种仅存在于肾脏中的模块。删除此模块的组件减少 Cyp 27 b1在肾脏中表达,但对非肾脏靶细胞中Cyp 27 b1的表达没有影响 (NRTC)。鉴于这些发现,我们提出以下分子研究。目标1:描述 介导Cyp 27 b1的小鼠肾脏内分泌模块及其单个组分 在体内通过PTH、1,25(OH)2D 3和FGF 23的表达和调节。我们将使用ChIP-seq分析, CRISPR/Cas9体内缺失研究,以进一步表征我们在研究中发现的调控模块。 肾脏,其功能是调节Cyp 27 b1的表达。我们还将定义独立的 Cyp 27 b1基因座中的模块,其介导NRTC中炎症信号传导的作用。这些 这些研究旨在促进我们对代谢的分子机制的理解, 激活维生素D。目的2:表征控制Cyp 24 a1表达的调控子模块 以及在体内通过PTH、1,25(OH)_2D_3和FGF_(23)在肾脏中的调节。Cyp 24 a1在肾脏中起着重要的作用。 在调节1,25(OH)2D 3和其他维生素D代谢物的血液水平中起协调作用。我们将使用 目的1中概述的方法来阐明该基因通过以下途径下调的基因组机制: PTH和上调的FGF 23和1,25(OH)2D 3。小鼠的突变分析将使我们能够确定 增强子簇和转录因子的作用位点以及负责 这些活动。目的3:利用饮食控制来检验和证实所提出的调节假说 在Cyp 27 b1受损的小鼠品系中与疾病相关。在这个目标中,我们计划测试一个假设 该模型解释了在删除基因组的组成部分后出现的复杂表型。 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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J WESLEY PIKE其他文献

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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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