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Prof. Dr. Philipp Koch

Stem Cell-based Models of Psychiatric Disorders

Psychiatric disorders are a heterogeneous group of mental illnesses associated with a high social and economic burden on patients and society. The complex etiology of these disorders, coupled with our limited understanding of the structural and functional abnormalities affecting the brains of neuropsychiatric patients, has made it difficult to develop effective medical treatment strategies. At the Hector Institute for Translational Brain Research (HITBR) we aim at leveraging the recent advances in stem cell technologies to develop cell-based models of mental disorders.

We make use of cellular forward and backward programming of patient-derived somatic cells into induced pluripotent stem cells (iPSCs), neurons and glia in order to generate cellular in vitro models of psychiatric diseases (2D as well as cerebral organoids). By merging iPS cell technology with multi-OMICs phenotyping, we try to understand the molecular mechanisms involved in the physiopathology of mental illnesses and to explore new drug targets. As reprogrammed cells carry the genetic background of a patient, they represent a valid platform to identify genetic predictors of drug responses and to associate cellular abnormalities with clinical phenotypes in a human context.

National and international Joint Research Projects

  • Prevention of neuronal protein aggregation through endogenous mechanisms1 (EndoProtect, BMBF)
  • A systems-medicine approach towards distinct and shared resilience and pathological mechanisms of substance use disorders (SysMedSUD, BMBF)
  • Deciphering alcohol addiction-associated gene regulation changes on a single cell level (DFG)

Selected publications

Ostermann L, Ladewig J, Müller FJ, Kesavan J, Tailor J, Smith A, Brüstle O, Koch P. In Vitro Recapitulation of Developmental Transitions in Human Neural Stem Cells. Stem Cells. 2019 Nov;37(11):1429-1440. doi: 10.1002/stem.3065. Epub 2019 Aug 24.

Giesselmann P, Brändl B, Raimondeau E, Bowen R, Rohrandt C, Tandon R, Kretzmer H, Assum G, Galonska C, Siebert R, Ammerpohl O, Heron A, Schneider SA, Ladewig J, Koch P, Schuldt BM, Graham JE, Meissner A, Müller FJ. Analysis of short tandem repeat expansions and their methylation state with nanopore sequencing. Nat Biotechnol. 2019 Dec;37(12):1478-1481. doi: 10.1038/s41587-019-0293-x. Epub 2019 Nov 18.

Poppe D, Doerr J, Schneider M, Wilkens R, Steinbeck JA, Ladewig J, Tam A, Paschon DE, Gregory PD, Reik A, Müller CE, Koch P*, Brüstle O*. (*corresponding author) Genome Editing in Neuroepithelial Stem Cells to Generate Human Neurons with High Adenosine-Releasing Capacity. Stem Cells Transl Med. 2018 Jun;7(6):477-486. doi: 10.1002/sctm.16-0272. Epub 2018 Mar 28.

Iefremova V, Manikakis G, Krefft O, Jabali A, Weynans K, Wilkens R, Marsoner F, Brändl B, Müller FJ, Koch P*, Ladewig J*. (*corresponding author) An Organoid-Based Model of Cortical Development Identifies Non-Cell-Autonomous Defects in Wnt Signaling Contributing to Miller-Dieker Syndrome. Cell Rep. 2017 Apr 4;19(1):50-59. doi: 10.1016/j.celrep.2017.03.047.

Doerr J, Böckenhoff A, Ewald B, Ladewig J, Eckhardt M, Gieselmann V, Matzner U, Brüstle O, Koch P. Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy. Mol Ther. 2015 Sep;23(9):1519-31. doi: 10.1038/mt.2015.106. Epub 2015 Jun 10.

Mertens J, Stüber K, Wunderlich P, Ladewig J, Kesavan JC, Vandenberghe R, Vandenbulcke M, van Damme P, Walter J, Brüstle O, Koch P. APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation. Stem Cell Reports. 2013 Dec 5;1(6):491-8. doi: 10.1016/j.stemcr.2013.10.011. eCollection 2013.

Ladewig J*, Koch P*, Brüstle O. (*shared first author) Auto-attraction of neural precursors and their neuronal progeny impairs neuronal migration. Nat Neurosci. 2014 Jan;17(1):24-6. doi: 10.1038/nn.3583. Epub 2013 Nov 17.

Mertens J, Stüber K, Poppe D, Doerr J, Ladewig J, Brüstle O, Koch P. Embryonic stem cell-based modeling of tau pathology in human neurons. Am J Pathol. 2013 May;182(5):1769-79. doi: 10.1016/j.ajpath.2013.01.043. Epub 2013 Mar 13.

Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P, Kögler G, Müller FJ, Koch P*, Brüstle O*. (*corresponding author) Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods. 2012 Jun;9(6):575-8. doi: 10.1038/nmeth.1972. Epub 2012 Apr 8.

Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, Poppe D, Doerr J, Ladewig J, Mertens J, Tüting T, Hoffmann P, Klockgether T, Evert BO, Wüllner U, Brüstle O. Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature. 2011 Nov 23;480(7378):543-6. doi: 10.1038/nature10671.

Contact

Central Institute of Mental Health

Square J5
68159 Mannheim

Phone: +49 621/1703 6711
E-Mail: philipp.koch@zi-mannheim.de

 

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