# Homeostatic Responses to Amino Acid Insufficiency

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2020 · $533,022

## Abstract

PROJECT SUMMARY
Dietary amino acid insufficiency (AAI) can yield a wide variety of outcomes that can be either adverse or
beneficial to health. A clearer understanding of the molecular factors and processes guiding homeostatic
control of the proteome (proteostasis) during AAI is essential to identify novel causes of improved stress
resistance and nutritional health. Collectively protein synthesis, proteolysis, and targeting are central to
proteostasis and AAI triggers stress signaling pathways that are central for cell adaptation. The overarching
hypothesis of this proposal is that the outcome of these key signaling networks that respond to AAI are vital to
controlling proteostasis and disease resistance. Cellular sensing of AAI involves overlapping signal
transduction mechanisms that are largely conserved from yeast to humans. Our published and preliminary
data demonstrate that key among these networks is the multi-part Integrated Stress Response (ISR), which
features translational and transcriptional gene expression networks directed by phosphorylation of eukaryotic
initiation factor 2. In the ISR network, the transcription factor ATF4 is central to directing the gene expression
programs that help ameliorate AAI. The objective of this application is to define the contribution of the ISR to
the early molecular and physiological responses that function to maintain proteostasis during dietary AAI. To
achieve the objective of this application we propose three Specific Aims: 1) Define how variations in AAI
activate the ISR; 2) Determine the role of ATF4 in the transcriptional networks and proteostatic responses to
AAI; and 3) Assess novel control of proteolysis by the ISR during AAI. To accomplish these aims, time course
studies will be conducted in cell lines and genetic strains of mice with targeted deficiencies in the ISR.
Analyses will utilize a combination of sophisticated molecular biology and stable isotope techniques to assess
and compare the mechanism of ISR activation and propagation in cell lysates and in the liver and skeletal
muscle of mice during AAI. The proposal is innovative in that it will reveal for the first time how the
transcriptome and translatome are guided by the ISR during AAI in vivo and provide insight into how the ISR
coordinates with other nutrient sensing networks to regulate protein balance. The work proposed is significant
because a greater understanding of the mechanisms activated by AAI will lead to new molecular targets and
approaches to better prevent or treat human diseases.

## Key facts

- **NIH application ID:** 9947925
- **Project number:** 5R01DK109714-05
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** Tracy G. Anthony
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $533,022
- **Award type:** 5
- **Project period:** 2016-09-20 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9947925

## Citation

> US National Institutes of Health, RePORTER application 9947925, Homeostatic Responses to Amino Acid Insufficiency (5R01DK109714-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9947925. Licensed CC0.

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