Koch P. BMBF - Bundesministerium für Bildung und Forschung : Gehirnorganeid-Tumor Hybrid Model (GBM3DTest) - Etablierung, Automatisierung und Substanztestung. 04/2024-03/2027.
BMBF - Bundesministerium für Bildung und Forschung 01EK2101B: Biomarker Evaluation Supporting Clinical Translation in schizophrenia (BEST), Subproject 3: Functional analysis of PBMCs and iPSC-derived neurons for the validation of schizophrenia biomarkers . 09/2021-08/2024.
An objectively measured and evaluated biomarker used as an indicator for a pathogenic process or
pharmacological response needs to achieve analytical and clinical validity. The latter depends on
qualifying measures linking peripheral biomarkers with a biological process and clinical endpoints of
schizophrenia. Thus, biomarker signatures identified in subprojects (SP) 1 and SP2 will be evaluated
and compared to schizophrenia-specific mechanistic endpoints in patient-derived neurons.
Schizophrenia is a neurodevelopmental disorder characterized by developmental deficits such as
impaired neuronal differentiation, reduced synapse densities in selected brain areas and
dysfunctional neuronal network activity. Since brain samples from patients are not accessible for
mechanistic biomarker validation in vitro, we apply neurons differentiated from patient-derived
induced pluripotent stem cells (iPSC) which faithfully represent the genetic background of individual
patients.
To this end, iPSC clones from patients with schizophrenia will be delivered by partners LMU and
CIMH. Diagnostic and imaging data as well as blood samples of the corresponding patients are at
hand and serve for sequencing blood transcriptomes and the establishment of multi-modal disease
signatures in SP1 and SP2. For biomarker validation, those iPSC specimens will be selected out of
the available ones which display the most similar disease signature as compared to signatures
obtained of the large scale patient cohorts in SP1 and SP2.
DFG - Deutsche Forschungsgemeinschaft : Deciphering alcohol addiction-associated gene regulation changes on a single cell level. 01/2020-12/2022.
Changes in brain structure and function that results from chronic exposure to alcohol suggest that neuroadaptive alterations in gene regulation substantially contribute to addictive behavior.
Transcriptional and epigenetic profiling of brain tissue from animal models and post-mortem human samples has identified multiple candidate genes to be dysregulated upon chronic alcohol exposure. However, a detailed assignment of those changes to specific cell types has not been performed due to technical limitations and lack of appropriate tissue. In this planned consortium, we will apply paralleled single cell sequencing to decipher transcriptional and epigenetic changes underlying alcohol addiction. We will perform single nuclei RNAsequencing (snRNA-seq) and snATAC-seq epigenetic profiling using postmortem tissue from a well-defined, high-quality brain bank of deceased alcohol addicts. We have previously established a novel snRNA-seq platform that allows isolating and sequencing of individual
nuclei from snap-frozen brain samples obtained from patients with other neuropsychiatric diseases. In parallel we will use standardized human iPSC-derived forebrain organoids from controls and alcohol addicts to monitor alcohol-induced changes in gene regulation and gene
expression in an isogenic (non-exposed vs. exposed; acute, chronic intermitting, acute withdrawal) forward approach. We expect that the proposed project will deliver the largest available database on alcohol addiction-associated gene regulation changes on a single cell level and help define critical contributors in the pathogenesis of alcohol addiction eventually eading to new therapeutic paradigms.