# Demystifying Disorders of Bicistronic Calcium Channel Genes

> **NIH NIH R35** · UNIVERSITY OF CHICAGO · 2020 · $993,747

## Abstract

Abstract
The long term objectives of this project are to explain the basis for the complex genotype-phenotype
relationships for a growing number of severe calcium channel gene disorders and develop therapies based on
these new insights. To make these advances we will capitalize on our new discovery that at least three of
these calcium channel genes are bicistronic i.e. they encode two distinct proteins, the calcium channel proteins
and a newly discovered transcription factor. We have discovered that the transcription factor is translated by
internal translation by a process resembling an internal ribosomal entry site (IRES). We hypothesize that
mutations in these Ca2+ channel genes may have a diversity of outcomes, affecting, in distinct cases,
neuronal firing, calcium signaling, regulation of the expression of the transcription factor or directly altering the
function of the transcription factor. In this study we will systematically explore the function and biological
action of these three novel transcription factors, how their expression is regulated by the IRES, how normal
cellular physiology governs their translocation to and from the nucleus, and how different mutations affecting
channel gating, IRES function and transcription factor cause impaired neuronal development and or viability in
these different disorders. We will study this using recombinant calcium channels expressed in primary neurons
and human reprogrammed neurons from normal and patient sources, and in transgenic mice expressing well
characterized mutations. We will study gene binding and expression using next generation approaches,
nuclear translocation using epitope and fluorescent tags with physiological stimuli, IRES function using dual
luciferase reporters and immunoblotting, neuronal development using immunofluorescent microscopy and
corrective therapy using antisense oligos, miRNA and AAV viral vectors expressing transcription factors.

## Key facts

- **NIH application ID:** 9986367
- **Project number:** 1R35NS116868-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Christopher Manuel Gomez
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $993,747
- **Award type:** 1
- **Project period:** 2020-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986367

## Citation

> US National Institutes of Health, RePORTER application 9986367, Demystifying Disorders of Bicistronic Calcium Channel Genes (1R35NS116868-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9986367. Licensed CC0.

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