# Targeting of proteins into peroxisomes

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $649,637

## Abstract

We are excited, if presented with the opportunity, by the prospect of continuing over 3 decades of research into
the mechanisms of peroxisome (PO) biogenesis. Our current work relies on yeast models, which have provided,
and will continue to reveal, deep insights into this conserved and important biological process in humans, while
also enhancing the diagnosis and understanding of the myriad of PO biogenesis disorders (PBDs). Our past
work has centered on PO homeostasis, which balances the biogenesis and turnover processes, but we focus
here on the birth of POs in cells that have no pre-existing POs, because previous genetic screens were done in
cells that generate POs by redundant pathways involving both growth and division of pre-existing POs and de
novo PO biogenesis. In doing so, redundant and essential genes were not identified, leaving a serious gap in
our understanding. We remedy this using a novel, innovative, high-throughput screen (HTS) for PO biogenesis
mutants in cells that are incapable of producing POs via growth and division. We show, using a pilot mini-screen,
that unlike previous screens, our strategy is yielding putative hits in many steps of PO biogenesis, while
identifying both known and novel genes, for the first time, including those involved in PO dynamics. This
promising HTS platform, which we validate by proof-of-concept experiments, has provided a treasure trove of
genes that now need deep investigation to understand how they function. Notably, many of the new genes we
identified interact with known players we and others have been investigating, and a significant number are
present at membrane contact sites (MCSs) between POs and other organelles. This presents a second
fascinating avenue of pursuit, wherein we will probe the importance of metabolite (especially lipids) transport
functions of the ER-PO MCSs. Our analyses will judiciously explore two yeast models to address evolutionary
conservation and derive common, conserved principles. This leads naturally to the third, poorly-explored arena
of interorganellar communication, for which we have found a novel, experimentally-tractable link, which is the
requirement of mitochondrial redox and oxidative phosphorylation (OXPHOS) for PO proliferation (i.e. increase
in PO number/cell). Thus, each of three new avenues of pursuit is expected to open new doors that will exceed
what we alone can understand, but our long-term vision is to create interesting, new, community opportunities
for future exploration in PO biology, knowing that it will be relevant, albeit indirectly, to patients with PBDs and
the alleviation of their suffering. This proposal represents an expansion of scope by synergizing our molecular
and cell biology efforts with the technical and intellectual prowess of the Aitchison laboratory (SCRI) and is
backed by a significant track record of advances made by both PIs in PO biology. The Aims of our proposal are:
Aim 1: Identify and perform functional studies on th...

## Key facts

- **NIH application ID:** 10875358
- **Project number:** 5R01DK041737-35
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** JOHN D. AITCHISON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $649,637
- **Award type:** 5
- **Project period:** 1990-05-10 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875358

## Citation

> US National Institutes of Health, RePORTER application 10875358, Targeting of proteins into peroxisomes (5R01DK041737-35). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10875358. Licensed CC0.

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