# Deciphering the role of phospholipid homeostasis in physiology and disease

> **NIH NIH K99** · ROCKEFELLER UNIVERSITY · 2024 · $91,500

## Abstract

PROJECT SUMMARY
Choline is a vitamin-like metabolite that is indispensable for cellular and organismal viability which must be
obtained through diet. Once imported into the cell, choline has multiple metabolic fates influencing diverse
cellular processes ranging from membrane biosynthesis to epigenetics. Choline it is a key constituent of
phospholipids, acetylcholine, and betaine which in turn impacts S-adenosylmethionine (SAM) and DNA
methylation. Despite the influence of choline on diverse cellular processes, the identity of a high affinity choline
transporter ubiquitously expressed across mammalian tissues was unknown. In our recently published
preliminary data, we utilized genome-wide association studies (GWAS) of serum metabolites to identify a poorly
characterized plasma membrane protein, feline leukemia virus subgroup C cellular receptor 1 (FLVCR1), as the
predominant choline transporter in mammals. In human cells and the developing mouse embryo, FLVCR1 loss
severely impacts choline metabolism resulting in depletion of betaine and phosphatidylcholine (PC) – the
predominant phospholipid species in cellular and organellar membranes. Mechanistically, FLVCR1 directly
transports choline into cells and we have recently used CryoEM to identify the residue necessary for transport.
In this effort, we also discovered that FLVCR1 can also transport ethanolamine, suggesting that it may also affect
phosphatidylethanolamine (PE) synthesis, the second most abundant membrane phospholipid. Taken together,
these data suggest that FLVCR1 is a crucial transporter for phospholipid metabolism. Broadly, this proposal
seeks to investigate the influence of phospholipid metabolism on cellular and organismal physiology.
 Utilizing a conditional knockout mouse, in Aim 1, we will study the role of FLVCR1 in organismal
physiology and metabolism and assess the efficacy of FLVCR1 as a target in metabolic disease. Our preliminary
data suggest that mitochondrial stress and activation of the integrated stress response are defining features of
cells and embryos lacking FLVCR1. In Aim 2 we will study how FLVCR1 loss and phospholipid metabolism
impacts mitochondrial function and the subsequent cellular stress response. In Aim 3 we seek to understand
how phospholipid homeostasis is maintained and regulated.
 Spanning basic biochemistry to mouse modeling, this application will address outstanding fundamental
questions in cellular metabolism and seek to apply these findings to the possible treatment of human disease.
The innovative studies proposed in this application in addition to the personalized training plan, will provide
rigorous scientific training and professional development which will enable my transition to independence and
start my own laboratory as a tenure-track professor.

## Key facts

- **NIH application ID:** 10949093
- **Project number:** 1K99DK140517-01
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Timothy Cole Kenny
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $91,500
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10949093

## Citation

> US National Institutes of Health, RePORTER application 10949093, Deciphering the role of phospholipid homeostasis in physiology and disease (1K99DK140517-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10949093. Licensed CC0.

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