# Supplement for Center for Synthetic Regulatory Genomics: Building CACNA1C alleles associated with Neuropsychiatric Disorders

> **NIH NIH RM1** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $382,563

## Abstract

Project Summary
The Center for Synthetic Regulatory Genomics (SyRGe) is tasked with development and application of
technology for making coordinated changes to large gene loci, broadly enabling investigations into the function
of regulatory sequences revealed by genome wide association study (GWAS) “hits”. The Center’s tools
dramatically supersede present technologies for manipulation and assessment of regulatory genome function
through its focus on assembly and delivery of so-called Big DNA. This supplement request proposes to
leverage our most recent technology development in Big DNA assembly and delivery to tackle a large locus in
CACNA1C, containing the top hits associated with various neuropsychiatric disorders, including schizophrenia,
bipolar disorder, major depression, ADHD and ASD. CACNA1C encodes a pore-forming subunit of the L-type
voltage-gated calcium channel and is widely expressed in neurons, endocrine cells, cardiomyocytes and
smooth muscles. Calcium influx through the channel is critical for synaptic plasticity, gene expression
regulation, insulin secretion and muscle contraction. In this supplement request, we propose to assemble and
deliver the ~330 kb human CACNA1C intron 3 to replace the mouse endogenous Cacna1c intron 3. We will
build and deliver human CACNA1C intron 3 that contains risk or protective alleles and differentiate the
engineered mouse ESCs into neurons for initial phenotyping. We will also build a series of variants for further
functional studies. We will assess the Cacna1c mRNA and L-type calcium current in differentiated neurons.
The proposed work in this supplement request will enable insights into the molecular mechanisms underlying
multiple neuropsychiatric disorders, and it will also serve as the foundation for further generation of humanized
Cacna1c mouse models for behavioral studies.

## Key facts

- **NIH application ID:** 10405299
- **Project number:** 3RM1HG009491-04S1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Jef D BOEKE
- **Activity code:** RM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,563
- **Award type:** 3
- **Project period:** 2018-06-12 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405299

## Citation

> US National Institutes of Health, RePORTER application 10405299, Supplement for Center for Synthetic Regulatory Genomics: Building CACNA1C alleles associated with Neuropsychiatric Disorders (3RM1HG009491-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10405299. Licensed CC0.

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