# The functional role of mTORC1 regulation by AMPK in cellular metabolic reprogramming

> **NIH NIH R35** · BAYLOR COLLEGE OF MEDICINE · 2024 · $400,000

## Abstract

PROJECT SUMMARY
 Loss of energy homeostasis is a key driver in human disease. Failure to maintain cellular energy balance
results in many disease states, including diabetes, cancer, and neurological diseases. AMP-activated kinase
(AMPK) is a highly conserved kinase responsible for maintaining cellular energy balance. Under conditions of
low nutrients and low energy, AMPK controls the metabolic switch from an energy-consuming anabolic state to
an energy-producing catabolic state at both the cellular and organismal level. Upon activation by energetic
stress, AMPK phosphorylates downstream targets to arrest cell growth, regulate transcription, inhibit protein
synthesis, and reprogram cellular metabolism. One of the most well-established downstream signaling pathway
inhibited by AMPK is the pro-growth mechanistic Target of Rapamycin complex 1 (mTORC1) pathway. However,
the functional role that mTORC1 inhibition plays in cellular metabolic reprogramming and maintaining energy
homeostasis upon AMPK activation is controversial, as both AMPK-independent inhibition of mTORC1 and
mTORC1-independent regulation of metabolic pathways have been described.
 The long-term scope of my research program is to elucidate the mechanisms that regulate energy
homeostasis and refine the current understanding of how pathways exert control of metabolic reprogramming.
To accomplish this long-term goal, my research group will address two major knowledge gaps in our current
understanding of how mTORC1 inhibition interacts with AMPK activity to drive cellular metabolism and growth:
 1) Is mTORC1 inhibition necessary for cellular metabolic reprogramming by AMPK? What aspects of
 cellular metabolic reprogramming require mTORC1 inhibition by AMPK?
 2) How does mTORC1 inhibition and AMPK activation coordinate the regulation of processes involved
 in metabolic reprogramming?
 My extensive expertise in defining molecular mechanisms of cellular processes and using innovative
mouse models makes my recently established independent laboratory an ideal environment to undertake these
efforts toward a more complete understanding of AMPK signaling. We will employ novel point-mutant mice
harboring specific serine-to-alanine mutations at the phosphorylation sites required for AMPK-dependent
inhibition of mTORC1. Using both mouse tissues and primary cells derived from these mice, we will perform
functional genomic and biochemical analyses to uncover the precise role of mTORC1 inhibition induced by
AMPK activation in regulating gene expression, autophagy, and lipid synthesis, which are critical for cellular
metabolic reprogramming. Together, these experiments will provide conceptual advances in how we think about
AMPK and its relationship with mTORC1 and will offer mechanistic insight into how dysregulation of these
pathways can lead to metabolic dysfunction and disease, which will allow us to identify new therapeutic strategies
for treatment of metabolically-linked human disease.

## Key facts

- **NIH application ID:** 10928173
- **Project number:** 5R35GM146762-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Jeanine L Van Nostrand
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2022-09-16 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928173

## Citation

> US National Institutes of Health, RePORTER application 10928173, The functional role of mTORC1 regulation by AMPK in cellular metabolic reprogramming (5R35GM146762-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10928173. Licensed CC0.

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