# Regulatory Mechanisms of Renal Vitamin D Activation and Degradation

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $392,728

## Abstract

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.

## Key facts

- **NIH application ID:** 10129366
- **Project number:** 5R01DK117475-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** J WESLEY PIKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $392,728
- **Award type:** 5
- **Project period:** 2018-04-11 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129366

## Citation

> US National Institutes of Health, RePORTER application 10129366, Regulatory Mechanisms of Renal Vitamin D Activation and Degradation (5R01DK117475-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129366. Licensed CC0.

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