# Harnessing bioelectric mechanisms of KRAS-dependent craniofacial abnormalities

> **NIH NIH F32** · TUFTS UNIVERSITY MEDFORD · 2020 · $72,450

## Abstract

RAS pathway mutations are linked to ~25% of all human cancers and cause birth defects that affect
approximately 1/1000 human births. Moreover, RAS has proven frustratingly intractable to classical genetic and
pharmaceutical approaches, establishing an urgent need for new approaches and therapies to understand and
treat RAS-driven disease. Exciting recent work, much of it from my new host lab (the Levin lab), has shown that
bioelectric signals can prevent and normalize RAS-driven tumors. Developmental bioelectricity has been
implicated in a range of developmental processes, including left-right patterning, brain morphogenesis, and eye
development. Moreover, bioelectric interventions stimulate regeneration in otherwise non-regenerative organs
and to induce formation of ectopic eyes throughout the body of a developing embryo. Craniofacial development
is one of the most striking examples of bioelectric signaling, which manifests as an endogenous 'Electric Face'
of dynamic patterns of de- and hyperpolarization that precede and instruct morphogenesis. A major knowledge
gap exists regarding how bioelectric signals interface with classical genetic pathways like RAS signaling. The
goal of this proposal is to understand the functional relationship between these crucial signaling nodes during
craniofacial development in the highly tractable Xenopus laevis model. The external development of Xenopus
facilitates bioelectric studies since membrane potential can only be measured in living cells. We observed that
ectopically activating the RAS pathway induces severe craniofacial abnormalities, and thus established Xenopus
as a model for RASopathies like Noonan syndrome. Aim 1 will be to characterize these craniofacial abnormalities
using both molecular-genetic and bioelectric approaches and integrating these findings into a computational
model comprising the KRAS pathway, bioelectric signaling, and transcriptional changes. Connecting bioelectric
and RAS signaling will both provide novel mechanistic insights to the pathology of RASopathies and inform future
experiments aimed at rescuing craniofacial abnormalities using bioelectric effectors. Aim 2 will test the
computational model in the context of functional experiments to repair RAS-induced craniofacial abnormalities.
The optogenetic approaches that have previously been successfully used to promote regeneration of tails and
prevent/normalize RAS-induced tumors will be exploited as new tools to repair RAS induced craniofacial defects.
Finally, the bioelectric circuitry of the developing face will be re-wired by altering connectivity patterns of gap
junctions (electrical synapses), as guided by the computational modeling, to restore proper craniofacial
morphology to embryos with RAS-induced defects. Thus, the key RAS and bioelectric developmental signaling
nodes will be integrated into a computational model, and the predictions made by this model will be used to
devise and test bioelectric interventions that will ...

## Key facts

- **NIH application ID:** 9929962
- **Project number:** 5F32DE027606-03
- **Recipient organization:** TUFTS UNIVERSITY MEDFORD
- **Principal Investigator:** Patrick T. McMillen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $72,450
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929962

## Citation

> US National Institutes of Health, RePORTER application 9929962, Harnessing bioelectric mechanisms of KRAS-dependent craniofacial abnormalities (5F32DE027606-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9929962. Licensed CC0.

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