# The Role of GATOR1 in Cortical Malformations

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $339,717

## Abstract

PROJECT SUMMARY
Malformations of cortical development (MCD) are a group of neurodevelopmental
disorders characterized by a range of morphological and structural abnormalities of the
cerebral cortex reflecting errors in embryonic brain development. MCD are associated
with medically refractory epilepsy and may require the surgical removal of the affected
brain tissue. Some MCD result from somatic mutations occurring in neuroglial progenitor
cells that result in abnormal cortical development in a restricted area of the brain known
as focal cortical dysplasia (FCD). In particular, somatic mutations affecting genes in the
mammalian target of rapamycin (mTOR) signaling pathway are highly associated with
FCD. Recently, mutations in the mTOR regulatory genes encoding the GATOR1
complex e.g., DEPDC5, NPRL2, NPLR3, have been associated with FCD. While
GATOR1 is known to modulate mTOR signaling in response to cellular amino acid levels
in non-neuronal systems, to date, no studies have investigated the functional role for
these genes in neurons or during brain development. Thus, in Aim 1, we will define the
effects of GATOR1 subunit knockdown (KD) on cell size and cell migration and assess
whether these effects are mTOR dependent. In Aim 2, we investigate the functional roles
of GATOR1 in protein synthesis, subcellular localization, and neuronal excitability. In
Aim 3, we assess how GATOR1 KD alters cerebral cortical lamination and generate a
new mouse model of FCD. We will show that FCD in this model can be prevented with
mTOR inhibitors. These studies will help to understand the role of GATOR1 during in
cortical development and provide pre-clinical assessment of mTOR inhibitors for
possible future use in GATOR1-associated epilepsies.

## Key facts

- **NIH application ID:** 10150099
- **Project number:** 5R01NS099452-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Peter B Crino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $339,717
- **Award type:** 5
- **Project period:** 2017-06-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150099

## Citation

> US National Institutes of Health, RePORTER application 10150099, The Role of GATOR1 in Cortical Malformations (5R01NS099452-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10150099. Licensed CC0.

---

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