# Peroxisomal fatty acid metabolism in genetic and age-related disorders

> **NIH NIH R00** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $249,000

## Abstract

Project Summary/Abstract
Peroxisomes are ubiquitous eukaryotic organelles that form a focal point for multiple metabolic pathways. Lipid
metabolism, and in particular, fatty acid transport related to it, depend heavily on peroxisomal membrane
proteins that have specifically evolved for such purposes. The ATP-dependent cassette (ABC) transporters of
‘D’ subfamily’ reside in the peroxisomal membrane and are responsible for fatty acid import into the
peroxisomes, defects in which process are related to various metabolic disorders. Mutations in ABCD1 cause
X-linked adrenoleukodystrophy (X-ALD) which manifests as mild to severe central nervous system (CNS)
demyelination. Dysfunction of ABCD3 and/or peroxisome biogenesis factors (PEXs) may cause Zellweger
syndrome (ZS), a heterogeneous group of peroxisome assembly disorders. In addition to inherited diseases,
reduced peroxisomal function is associated with aging and pathogenesis of age-related acquired diseases like
diabetes, neurodegenerative disorders. Key gaps in understanding the function of ABCDs in metabolism and
disease are due to lack of structural details, particularly of their conformational plasticity during substrate
transport, and how this is compromised during aging and disease. My goal is to understand the involvement
of peroxisomal fatty acid metabolism in aging and age-related neurodegenerative diseases, specifically
Alzheimer’s disease and ultimately to lead a research group as an independent researcher in this area.
I propose to elucidate the structural basis for function of ABCDs at atomic level using CryoEM in the absence
and presence of substrate, and ATP (Aim 1a and 1b, mentored), coupling between ATPase and thioesterase
activity, and fatty acid binding and transport (Aim 2a and 2b, mentored). I will determine atomic structures of
ABCDs in complex with PEXs (Pex3 and Pex19) using CryoEM (Aim 3a, mentored) and assess alterations in
peroxisomal morphology using Cryo-Electron Tomography; function and membrane composition of ABCD(1-3)
knockdown cell lines, aged cells and Alzheimer’s disease (AD) model cell lines (Aim 3b, 3c, 3d mentored/
independent phase). These aims foster my long-term aim of studying peroxisome function and its relation to
cellular physiology and disease, while obtaining training and experience in forefront tools of structural
biophysics. For executing these aims, I have support of a very strong team of mentors, consultants and
advisors. My mentor Prof. Robert Stroud is a pioneer in membrane protein structure and mechanism, my co-
mentor Prof. Peter Walter is a pioneer in the unfolded protein response (UPR) and specializes in cell and
organelle biology. My co-mentor Dr. Adam Frost is at the forefront of CryoEM/CryoET. Consultant Prof. Eric
Verdin is a leading scientist in aging. Consultant Prof. Martin Kampmann is discovering new molecular players
in AD. Scientific advisors Prof. Yifan Cheng pioneered CryoEM and Prof. Charles Craik has developed
antibody and Fab l...

## Key facts

- **NIH application ID:** 11094167
- **Project number:** 4R00AG070271-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Meghna Gupta
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2022-02-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11094167

## Citation

> US National Institutes of Health, RePORTER application 11094167, Peroxisomal fatty acid metabolism in genetic and age-related disorders (4R00AG070271-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11094167. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*