# Regulation of cell fate and function by sterol homeostasis

> **NIH NIH P20** · SANFORD RESEARCH/USD · 2020 · $306,202

## Abstract

PROJECT SUMMARY
Loss of cholesterol homeostasis has been associated with a host of neurodevelopmental and neurodegenerative
disorders, though the precise mechanisms underlying cholesterol-mediated effects are unclear. While inherited
mutations within cholesterol synthetic enzymes are known to induce neurodevelopmental deficits, the
mechanisms behind cellular phenotypes resulting from these biochemical deficits remain largely undefined at
the cellular and functional level. Therefore, studies delineating the role of cholesterol metabolism in
neurodevelopment and function could have a significant impact on our understanding of potential common
mechanisms of disease pathogenesis. Stem cell models exhibiting biochemical defects in the cholesterol
synthetic pathway represent a novel biological model to study interactions between abnormal sterol levels and
signaling events leading to cellular and functional deficits. Using induced pluripotent stem cell (iPSC) models
exhibiting DHCR7 and SC5D mutations, we recently uncovered a unique regulatory role for sterol biosynthesis
in the functional interactions between proteins mediating Wnt/β-catenin signaling. Within this proposal, we will
test the hypothesis that defects in cholesterol synthesis inhibit normal neurodevelopment at the stem cell level
through inhibition of protein-protein interactions, shifting differentiation patterns toward neuronal cell types at the
expense of glial cells while inhibiting synaptic function. Aim 1 of this project will utilize genomic sequencing and
functional studies in human iPSC derivatives and rodent models to define how defects in cholesterol homeostasis
regulate neural specification and function. Aim 2 will correlate the cellular effects of altered cholesterol
homeostasis with disrupted protein-protein interactions through biochemical analyses of protein-lipid
interactions., In vivo cellular models will also define the kinetics, specificity, and downstream signaling events
resulting from cholesterol defects. These experiments will significantly advance our understanding of the role of
cholesterol and associated signaling in regulating neurodevelopment and neuronal function, while potentially
elucidating the mechanistic underpinnings of cholesterol homeostatic changes in common neurological
diseases.

## Key facts

- **NIH application ID:** 10004076
- **Project number:** 5P20GM103620-08
- **Recipient organization:** SANFORD RESEARCH/USD
- **Principal Investigator:** Kevin Richard Francis
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,202
- **Award type:** 5
- **Project period:** 2013-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004076

## Citation

> US National Institutes of Health, RePORTER application 10004076, Regulation of cell fate and function by sterol homeostasis (5P20GM103620-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10004076. Licensed CC0.

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