# Translational regulation of PGC1alpha and oxidative metabolism

> **NIH NIH K99** · DANA-FARBER CANCER INST · 2022 · $90,000

## Abstract

PROJECT SUMMARY
As the prevalence of obesity and associated disorders rises, manipulation of adipocyte energy expenditure has
gained attention as a potential means to treat metabolic disease. This strategy leverages the physiology of
thermogenic adipocytes, a cell type that relies on oxidative phosphorylation metabolism to drive futile chemical
cycles that release energy as heat. Recent work has suggested the potential for ribosomal control of
thermogenic gene expression. Elucidating the responsible mechanisms may reveal novel means to manipulate
adipocyte metabolism for the treatment of obesity and diabetes. This proposal tests the hypothesis that the
distinct metabolism of thermogenic fat is enabled by specialized mRNA translation preferences inherent in this
cell type. A first set of studies focuses on a single mRNA, PPARGC1A, and aims to purify the proteins that
confer its cell-type-specific translational output. This mRNA encodes PGC1α, a dominant regulator of
mitochondrial biogenesis. A second set of studies develops an in vivo mouse model to test the hypothesis that
the helicase DDX3X, a regulator of mRNA translation and cytoplasmic stress granules, is a thermogenic-fat-
selective translational regulator that supports expression of genes critical for oxidative metabolism. A third set
of studies uses ribosome profiling technology to define the global mRNA translation dynamics associated with
thermogenic activation. Together, these studies expand the scope of my work while generating foundational
datasets and mouse models for my scientific independence. They will be carried out in the lab of a recognized
leader in the field of molecular metabolism, Dr. Bruce Spiegelman, at the Dana-Farber Cancer Institute and
Harvard Medical School. In this rich environment, I will benefit from a mentorship team committed to instruct
me in: adipocyte biology, including in vivo genetic manipulation; mouse metabolic phenotyping; mass
spectrometry; and bioinformatics. The technical training is complemented by formal instruction in human
metabolic pathophysiology, as well as activities for honing my leadership, speaking, and writing skills. In this
way the NIH Pathway to Independence Award supports my transition from mentored work to an independent
stage in which I intend to use cutting-edge methods to broadly define the translational dynamics of
thermogenic fat, identify the responsible regulators, and test how post-transcriptional dynamics such as stress
granule assembly may contribute. My ultimate goal is to lead an academic research group that investigates
how the gene expression programs that define cellular identity and metabolism are established, how they are
perturbed in metabolic disease, and how they may be therapeutically manipulated to prevent or treat metabolic
disease.

## Key facts

- **NIH application ID:** 10399645
- **Project number:** 5K99DK125722-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Phillip Anthony Dumesic
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $90,000
- **Award type:** 5
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399645

## Citation

> US National Institutes of Health, RePORTER application 10399645, Translational regulation of PGC1alpha and oxidative metabolism (5K99DK125722-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399645. Licensed CC0.

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