# Elucidating the neuropathophysiology of TSC using genetically engineered human neurons

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $323,566

## Abstract

PROJECT SUMMARY
 Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1
or TSC2 genes. The protein products of TSC1 and 2 form a complex that is a key negative regulator of mTOR
signaling. TSC is associated with an array of neurological and psychiatric problems that can include epilepsy,
autism spectrum disorder, and intellectual disability. The neurological manifestations of TSC are amongst the
most debilitating to patients, yet our knowledge of the neuropathophysiology of TSC is limited. Animal models
of TSC have been valuable to address questions of basic biology, revealing alterations in neuronal
development, morphology, and synaptic communication. The next major challenge is to translate these
findings to humans. This will require defining the consequences of TSC mutations in a human genetic and
developmental context. To achieve this we will establish a novel human neuronal model for TSC based on
Cas9-mediated gene editing of human embryonic stem cells (hESCs). To this end we have generated an
isogenic panel of hESCs with heterozygous, homozygous, and conditional loss of function mutations in the
TSC1 or TSC2 genes. These cells will be differentiated into neural progenitors, neurons, and cerebral
organoids to model the early stages of human cortical development when TSC-related phenotypes first arise.
We will determine how mutations in TSC1 or 2 affect the development and function of human neurons using
biochemical, genome-wide profiling, imaging, and electrophysiological approaches. Our findings will answer
several key questions related to genotype-phenotype relationships in TSC and the developmental origin of the
cortical malformations that are a hallmark of this disorder. In addition, the cell lines we generate will be a
valuable resource for the research community to investigate disease mechanisms and test potential
therapeutics for TSC and other “mTOR-opathies” directly in primary human cells.

## Key facts

- **NIH application ID:** 9870965
- **Project number:** 5R01NS097823-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Helen S. Bateup
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $323,566
- **Award type:** 5
- **Project period:** 2016-05-15 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870965

## Citation

> US National Institutes of Health, RePORTER application 9870965, Elucidating the neuropathophysiology of TSC using genetically engineered human neurons (5R01NS097823-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870965. Licensed CC0.

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