Transcriptional Regulation Assessed in Neuronal Subtypes in three major interrelated Psychiatric disorders

Introduction

Schizophrenia (SCZ), bipolar disorder (BP), and Major Depressive Disorder (MD) are three major psychiatric disorders that affect mood, thinking, and behavior. These disorders are strongly genetically intercorrelated and exhibit pronounced clinical overlap, suggesting that they are different manifestations of a shared underlying neurobiology, along a spectrum.

Challenges in Understanding

However, the neurobiological mechanisms and pathophysiology of these disorders are still poorly understood, limiting effective drug discovery. There is an urgent need for new models for drug testing, as:

1. Animal models have major limitations.
2. Current psychiatric organoid systems are dependent on patient-derived stem cells, in which technical, genetic, and biological diversity confound the interpretation and obscure the underlying neuropathology.

Proposal Overview

The major challenge of this ERC proposal is to develop organoid models for psychiatric disorders by targeting upstream transcription factors. Transcription factors are key molecules that drive cell type differentiation, including neuronal network formation.

Central Hypothesis

Hence, the central hypothesis of this ERC proposal is that neuronal subtype-associated transcription factors can function as targets to model these disorders using brain organoids. However, the neuronal transcriptional regulators that mediate these disorders are currently unknown and difficult to identify.

Methodology

Novel genomics technologies allow for an unbiased characterization of the brain in order to detect cell types and genes that are dysregulated in disease. These technologies can be used to identify putative upstream transcription factors.

Proposed Strategies

Here, I propose a selection of multi-omics profiling strategies to a unique collection of high-quality psychiatric human brain tissue aimed at reliably identifying key upstream transcription factors. We will subsequently target those transcription factors in brain organoid systems to establish neurobiological models of these disorders.