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

基本信息

  • 批准号:
    9904622
  • 负责人:
  • 金额:
    $ 23.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT FGF23 represents a recently discovered phosphaturic hormone whose primary physiological role is to regulate phosphate content in the blood through direct actions in the kidney. FGF23 is expressed in osteoblasts and osteocytes where its output is controlled by phosphate, 1,25(OH)2D3, and PTH. More recent studies now suggest that inflammation and iron deficiency also upregulate FGF23 expression from multiple sources. Despite considerable effort, however, little is known of the mechanisms through which the above regulators modulate FGF23 expression. Using ChIP-seq analysis, we discovered 5 regulatory regions located at distal sites across the mouse FGF23 gene locus that we hypothesized were responsible for FGF23 regulation in vivo. We deleted each of these potential regulatory regions in the mouse genome using CRISPR/Cas9 methods, and have explored their role in mediating the actions of phosphate, 1,25(OH)2D3, PTH and LPS via loss of function studies through these segments in vivo. Our results support a proposal aimed at defining the molecular mechanisms which underlie FGF23 regulation in health and disease. Aim 1: Refine the functional actions and interactions of regulatory enhancers at the FGF23 gene locus that control tissue FGF23 expression in vivo. Several additional strains of regulatory mutant mice will be created using a CRISPR/Cas9 approach and response to phosphate, PTH, 1,25(OH)2D3 and LPS assessed to refine and potentially resolve the genomic sites of action for each of these regulators, and to determine whether regions already identified comprise the entire regulatory domain at the FGF23 locus. These studies will firmly establish the span of functional regulatory activities involved in FGF23 expression. Aim 2: Determine the transcription factors, chromatin regulators and signaling pathways and their interactions that mediate the regulation of FGF23 expression in tissues in vivo. We will use ChIP-seq and ATAC-seq analyses and other techniques to resolve DNA sites of action, enabling the unbiased identification of motifs, transcription factor and chromatin coregulators, and potential signaling pathways that are involved. Aim 3: Identify the temporal role(s) of systemic factors in the regulation of FGF23 expression in an oxalate-induced mouse model of chronic kidney disease. Oxalate-induced acute kidney disease impacts the expression of FGF23 from bone and other tissues. We will examine the ability of oxalate to induce FGF23 expression in tissues as a function of our FGF23 regulatory deletion models. These studies will also focus on assessing the systemic and biological phenotypes that emerge in kidney, skeleton and the vascular system due to amelioration of FGF23 upregulation following oxalate treatment. Our results are likely to provide greater insight into the selective mechanisms through which FGF23 is regulated in vivo in health and disease.
项目总结/文摘

项目成果

期刊论文数量(0)
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专利数量(0)

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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

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:
    $ 23.25万
  • 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:
    10373006
  • 财政年份:
    2018
  • 资助金额:
    $ 23.25万
  • 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:
    $ 23.25万
  • 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:
    $ 23.25万
  • 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:
    $ 23.25万
  • 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:
    $ 23.25万
  • 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:
    $ 23.25万
  • 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:
    $ 23.25万
  • 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:
    $ 23.25万
  • 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:
    $ 23.25万
  • 项目类别:

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    Grant-in-Aid for Challenging Exploratory Research
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