# Development of a novel rodent model of hypothalamic hamartoma and epilepsy

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $419,375

## Abstract

ABSTRACT: Hypothalamic Hamartomas (HH) are noncancerous growths of disorganized cells and are believed
to result as a consequence of somatic mutations in sonic hedgehog (SHH) pathway genes during embryonic
development. HH are associated with gelastic seizures (GS) that are difficult to control with existing anti-seizure
drugs, and people with HH also go on to develop even more severe pharmacoresistant seizure types due to
secondary epileptogenesis. Thus, there is a significant clinical need to develop new therapies to treat the
debilitating pharmacoresistant seizures that result as a direct consequence of HH and/or that develop following
secondary epileptogenesis. A complete absence of animal models that recapitulate the phenotypes resulting
from HH is a significant reason why discovery and development of novel pharmacological treatments has been
hindered. The present R21 proposal seeks to solve this problem by generating a novel mouse model of HH for
use in therapy discovery. This goal will be accomplished by utilizing tamoxifen-inducible Cre-Lox recombination
to independently express and test two etiologically relevant somatic mutations in SHH signaling molecules during
periods of peak hypothalamic cellular proliferation and examine resultant hypothalamic anatomy, gene
expression, and physiology in these mice. Since activation of SHH signaling is known to promote cell
proliferation, Aim 1 will independently examine the effects of expressing SmoM2 (a constitutively activated form
of the Smoothened GPCR) that will produce a cell autonomous upregulation of SHH signaling in a mosaic of
affected cells in the developing hypothalamus. Aim 2 will independently examine the effects of expressing a
truncated version of the SHH pathway transcription factor GLI3 (GLI3T) that has been shown in resected HH
tissues. Expression of GLI3T acts as a constitutive repressor and is expected to downregulate SHH signaling.
Downregulation of SHH signaling in a limited number of cells may not conflict with our hypothesis that an overall
upregulation of SHH signaling is responsible for the development of HH because, as it has recently been
demonstrated, a loss of SHH signaling in a mosaic of developing hypothalamic cells can cause a cell non-
autonomous upregulation of SHH signaling in neighboring wild-type cells. Therefore, this R21 proposal will utilize
existing mouse lines to directly test the hypothesis that development of HH and consequent seizure phenotypes
can result from somatic mutations that produce either a cell autonomous or non-autonomous upregulation in
SHH signaling during hypothalamic development. Thus, this work has the potential to provide the field with the
first animal model of HH and sets the stage for future work to determine novel therapeutic approaches for the
treatment of refractory seizures and to examine the mechanisms underlying secondary epileptogenesis.

## Key facts

- **NIH application ID:** 10354125
- **Project number:** 1R21NS125211-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** PETER J WEST
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $419,375
- **Award type:** 1
- **Project period:** 2021-09-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354125

## Citation

> US National Institutes of Health, RePORTER application 10354125, Development of a novel rodent model of hypothalamic hamartoma and epilepsy (1R21NS125211-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10354125. Licensed CC0.

---

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