# Exploring a Novel Paradigm of Schizophrenia and Bipolar Disorder

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $936,323

## Abstract

Summary
Schizophrenia and bipolar disorder are among the most clinically defined but least understood psychiatric
disorders. We have uncovered a novel pathway of stress regulation in the brain mediated by the master
transcriptional repressor REST/NRSF. Our preliminary studies suggest that the REST pathway may be
dysregulated in the brains of patients with schizophrenia and bipolar disorder, and that treating bipolar patients
with lithium, a drug that activates REST, restores homeostasis. This project will address a novel conceptual
paradigm that might underlie both disorders involving dysregulation of a stress response system in the brain
that is regulated by REST. Initially, we will determine if REST function is altered in neurons derived from
induced progenitor stem (iPS) cells of patients and in isogenic iPS cell lines in which we have introduced a
schizophrenia-causing genetic variant using the CRISPR-Cas9 system. We will then determine if conditional
knockout mouse models of REST dysfunction in specific neuronal subpopulations recapitulate behavioral,
metabolic and physiological changes associated with schizophrenia and bipolar disorder. Finally, we will
define transcriptome changes in the brains of schizophrenic and bipolar patients at single neuron resolution to
ascertain the role of REST and other transcriptional regulators in specific neuronal cell types. To accomplish
this goal, we will advance a new technology we have recently developed called fluorescence in situ
sequencing of RNA (FISSEQ). In contrast to conventional sequencing, which requires isolation of DNA or
RNA, FISSEQ sequences RNA in intact tissue, bringing together the depth of transcriptome-wide RNA
sequencing with the resolution of single molecule in situ RNA localization. FISSEQ can also be multiplexed
with other data streams, particularly proteomics, enabling multidimensional interrogation at single cell
resolution. FISSEQ will be used to derive reference transcriptomes for identified neural cell types in the human
and mouse brain. Differences between reference transcriptomes and transcriptomes of patients with
schizophrenia and bipolar disorder may implicate REST or other transcription factors, and provide a systems-
level view of the central regulatory pathways. This will be complemented by transcriptome analysis in mice
genetically engineered to delete or overexpress the REST gene in specific neuronal populations. Although this
approach will be used to explore psychiatric disorders, once developed, it could be rapidly employed to
elucidate altered genome regulation in any brain disorder. These studies will bring together two principal
investigators with complementary areas of expertise in a multidisciplinary approach to understand psychiatric
disorders and advance single cell transcriptome analysis of the brain.

## Key facts

- **NIH application ID:** 9981018
- **Project number:** 5R01MH113279-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** GEORGE M CHURCH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $936,323
- **Award type:** 5
- **Project period:** 2016-09-26 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981018

## Citation

> US National Institutes of Health, RePORTER application 9981018, Exploring a Novel Paradigm of Schizophrenia and Bipolar Disorder (5R01MH113279-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981018. Licensed CC0.

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