# Cell-specific analysis of sub-kinomes in schizophrenia

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2020 · $339,585

## Abstract

Project Summary:
This is a revised R01 application to investigate abnormalities of signaling networks in pyramidal neurons in
schizophrenia. It is an understatement to say that the treatment of schizo-spectrum disorders has not
progressed in the past 25 years, since the development of atypical antipsychotics. However, there is broad
consensus that these newer medications do not extend the efficacy of pharmacological treatments to cognitive
and negative/deficit symptoms, which lead to profound disability in a large number of persons afflicted with
schizophrenia. While effective for the psychotic, or positive symptoms, all antipsychotic medications are
associated with significant side effects, and have high rates of discontinuation. We posit that abnormalities of
cortical pyramidal neurons underlie many of the cognitive deficits observed in the schizophrenia phenotype,
including abnormalities of working memory, executive function, and motivation. Pyramidal neurons typically
project to other cortical regions (superficial pyramidal cells, in layers II and III) or subcortically (deep pyramidal
cells, in layers V and VI) to the thalamus, striatum, and other basal ganglia. Divergent abnormalities of
superficial and deep pyramidal neurons in schizophrenia may arise from neurodevelopmental insults that
reflect differences in the circuitry of these cell types, resulting in altered gene expression profiles, neuronal
migration, and/or aberrant connectivity of these neurons. We hypothesize that abnormalities of pyramidal
neurons extend well beyond simple measures of gene expression, and include disease- and lamina- specific
changes in functionally related signaling networks. To address this problem, we adapted a novel “omics”
bioinformatics approach for analysis of serine/threonine sub-kinomes in postmortem brain tissue, and identified
high-yield protein kinase targets for further study. We propose to focus in this application on two of our high-
yield “hits” from these hypothesis generating preliminary studies: AKT and PKA. Specifically, we will test the
hypothesis that these kinases are differentially regulated in superficial and deep pyramidal neurons in
schizophrenia. We will use an innovative approach that combines standard techniques, including laser capture
microdissection and biochemical kinase activity assays, to measure pyramidal neuron-specific kinase
expression and activity in schizophrenia. We will follow up on these studies by measuring expression of factors
downstream from AKT and PKA, including phosphoproteins and related networks of mRNAs. Finally, we
propose two discrete in silico studies, one focused on developing pyramidal neuron-specific signaling models
in schizophrenia, and the other focused on integration of our data with cutting-edge bioinformatics databases,
to identify pathways associated with standardized pathophysiological disease-drug dyads. These innovative
studies will identify pyramidal neuron-specific signaling pathways disru...

## Key facts

- **NIH application ID:** 9926312
- **Project number:** 5R01MH107487-06
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** JAREK MELLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,585
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926312

## Citation

> US National Institutes of Health, RePORTER application 9926312, Cell-specific analysis of sub-kinomes in schizophrenia (5R01MH107487-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9926312. Licensed CC0.

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