# A Drosophila Model for the Regulation of Aerobic Glycolysis

> **NIH NIH R35** · TRUSTEES OF INDIANA UNIVERSITY · 2020 · $382,844

## Abstract

Project Summary
Many human diseases are characterized by dramatic changes in metabolism, an observation that is
particularly evident in cancer, where rapidly proliferating cells become highly dependent on glucose
metabolism. Cancer cells, however, do not use increased levels of glycolysis to generate energy, but rather
shuttle metabolic intermediates through biosynthetic pathways and rely on lactate fermentation to maintain
high levels of glycolytic flux. This phenomenon, known as aerobic glycolysis or the Warburg effect, allows
cancer cells to metabolize large quantities of glucose in order to generate the biomass required for cell growth
and proliferation. The manner in which cancer cells rely on glucose metabolism suggests that this metabolic
state could be exploited for therapeutic intervention and has become a focal point in cancer research. I have
discovered that the fruit fly Drosophila melanogaster also uses aerobic glycolysis to promote growth and have
established Drosophila as a model system for studying the genetic mechanisms that regulate this metabolic
program. My initial efforts using this model have proven successful, as I have determined that the Drosophila
Estrogen-Related Receptor (dERR) is a master regulator of aerobic glycolysis. My lab will now expand upon
these initial observations to identify the molecular mechanisms that both activate and repress aerobic
glycolysis in vivo. Furthermore, we have determined that Drosophila larvae use aerobic glycolysis to
synthesize the oncometabolite L-2-hydroxyglutarate (L-2HG). This compound is almost exclusively studied in
the context of cancer metabolism and the endogenous roles of L-2HG remain unexplored. We will determine
how L-2HG synthesis is controlled in vivo and explore how this oncometabolite controls normal animal growth.
Finally, we will use a combination of genetics, genomics, and metabolomics to determine how the disruption of
key reactions in aerobic glycolysis affects growth and physiology. Many of these enzymes represent potential
therapuetic targets and our innovative approach provides a rare opportunity to systematically evaluate the
effects of inhibiting individual glycolytic enzymes in a whole animal system. Moreover, our studies also explore
the compensatory metabolic pathways that are activated in response to decreased glycolytic flux, which in a
clinical setting, could render tumors insenstive to drug treatments. Finally, we have uncovered an unexpected
correlation between the repression of aerobic glycolysis, increased levels of fatty acid oxidation, and pyrimidine
metabolism. My lab will use this unexpected discovery as a foundation to explore the poorly understood role of
fatty acid beta-oxidation in nucleotide production. Our studies will allow, for the first time, a genetic dissection
of the mechanisms regulating aerobic glycolysis within the context of normal animal development, and will
potentially uncover novel approaches to control cellular growth at a met...

## Key facts

- **NIH application ID:** 9982382
- **Project number:** 5R35GM119557-05
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Jason Michael Tennessen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,844
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982382

## Citation

> US National Institutes of Health, RePORTER application 9982382, A Drosophila Model for the Regulation of Aerobic Glycolysis (5R35GM119557-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982382. Licensed CC0.

---

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