# Novel Components of the mTORC1 and mTORC2 Pathways

> **NIH NIH R01** · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · 2021 · $487,500

## Abstract

The mTOR kinase is the central component of a signaling pathway that controls mass accumulation
and metabolism in response to the nutritional state of organisms. The pathway is deregulated in many
common human diseases, including cancer, epilepsy, and diabetes, and is also well established to
modulate the aging process. Pharmacological or genetic suppression of mTOR is amongst the best-
validated approaches for increasing the lifespan of diverse organisms. The mTOR protein kinase is the
target of the drug rapamycin and the catalytic subunit of two large protein complexes, mTOR Complex 1
(mTORC1) and 2 (mTORC2), that control separate branches of the pathway and preferentially respond
to different stimuli. mTORC1 responds to diverse signals, including many types of growth factors,
nutrients, and stresses, and regulates the balance between major anabolic and catabolic processes,
including protein, nucleotide, and lipid synthesis as well as autophagy, respectively. Recently, we
discovered many of the components through which mTORC1 senses nutrients and we are just starting
to understand the role of the nutrient-sensing pathway in vivo. Our preliminary data show that the
appropriate regulation of mTORC1 by nutrients is essential for mice to adapt to diets low in the essential
amino acid leucine. Moreover, we have evidence that mTORC1 is spatially controlled in unexpected
ways in tissues in vivo and that novel in vivo regulatory mechanisms remain to be discovered.
 The goals of our proposed work are to understand why the capacity of mTORC1 to sense leucine
deprivation is important for mice to adapt to a leucine-free diet (Aim 1) and the role of
compartmentalized nutrient sensing in the control of tissue physiology and metabolism (Aim 2). In
addition, we will exploit in vivo proteomics and genetics to identify novel mTORC1 regulators in the liver
(Aim 3). We will accomplish our goals with a multi-disciplinary approach that exploits biochemistry,
metabolomics, proteomics, molecular biology, and mouse engineering. Our results should increase our
understanding of a central growth regulator in vivo and reveal novel regulatory mechanisms that may
have value as therapeutic targets.

## Key facts

- **NIH application ID:** 10114955
- **Project number:** 5R01AI047389-22
- **Recipient organization:** WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
- **Principal Investigator:** JONATHAN S. WEISSMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $487,500
- **Award type:** 5
- **Project period:** 2000-04-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114955

## Citation

> US National Institutes of Health, RePORTER application 10114955, Novel Components of the mTORC1 and mTORC2 Pathways (5R01AI047389-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10114955. Licensed CC0.

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