Department of Child and Adolescent Psychiatry
University of Zurich
The Neurobiochemistry Laboratory
We are interested in finding risk factors and biomarkers for child and adolescent psychiatric disorders such as attention-deficit hyperactivity disorder (ADHD), early-onset obsessive-compulsive disorder (OCD) or Autism spectrum disorders (ASD). As well as early detection and prevention of psychosis. In addition, the laboratory focuses on functional mechanisms of action of specific mutations found to associate to a specific disorder as well as mechanism of action of drug therapies on neuronal development.
Keywords: Molecular biology, epigenetics, neuronal cells, child and adolescent psychiatry, biochemistry, ADHD, OCD, Autism, psychosis.
1 Senior researcher, 1 Technician, 2 Post docs, 2 Master students
We focus on finding risk factors and biomarkers for child and adolescent psychiatric disorders such as attention-deficit hyperactivity disorder (ADHD), early-onset obsessive-compulsive disorder (OCD) or Autism spectrum disorders (ASD). Such knowledge will provide an additional tool for early and differential diagnosis of these disorders. In addition, finding specific biomarkers for therapy response in these disorders is in the focus of the research, since this will provide a better prediction of therapy response. Since these disorders have high heritability, it is assumed that genetic alterations have a great role in the development of these disorders. Still it was also been shown that environmental factors play a role, as in twin and family studies. Therefore, in the fist aspect both genetic findings (e.g. polymorphisms, copy number variation (CNVs)) as well as epigenetic findings (e.g. DNA methylation alterations) combined with some functional findings (e.g. transcription alterations) in peripheral samples (e.g. blood, saliva) are investigated in these disorders as well in the different therapies.
In addition, we investigate the functional effect of the highly significant associated SNP on the HTR2A receptor and early-onset OCD. For this, both neuronal cell lines as well as primary cell lines are investigated for the effects of HTR2A agonists on cell survival and further downstream proteins. In parallel, lymphoblastoids from OCD patients comparing to controls are studies for the functional effect of the specific mutation on the HTR2A. In a similar manner, the transcriptional effects of the HTR2A SNP in post-mortem brain tissue will be studied in different ages (from embryos to old age). Such, studies might reveal the functional relevance of our clinical association finding in early-onset OCD and this gene.
Another example for such functional study, involves the therapy of ADHD with stimulants (e.g. methylphenidate (MPH)). MPH is one of the common drug therapy for ADHD. Currently it is assumed that the major mechanism of action of MPH derives from its inhibition of the dopamine transporter (DAT) as well as partial inhibition of the norepinephrine transporter (NET) and the serotonin transporter (SERT). Although MPH was introduced about 50 years ago, no conclusive data are currently available to assess the short- and long-term effects on the CNS development or its mechanism of action. In Switzerland, prescription of MPH increased significantly between the years 2006 until 2009. According to recent data of the Swiss insurance provider Helsana, which can be assumed representative for the Swiss population, prescriptions of MPH increased more than 30% in children and adolescents (7-18 years of age) during this four year period. In addition it is estimated, depending on MPH delivery that about 30% of ADHD patients do not tolerate or respond to stimulant medication. Since the knowledge from animal models and clinical studies point to a paradoxical effect of MPH and DAT inhibition, it is expect that additional new targets in which MPH exerts its effect could be revealed. Therefore, neuronal cell culture studies of MPH mechanism of action and its additional targets is one of the research themes in my laboratory. This is studies in neuronal cells devoid of DAT (using knock out techniques) combined with pharmacogenetic and neurochemistry analysis. Such new targets could be of benefit for the clinical studies as well as for new drug therapy developments.
In addition, we collaborate with groups in Switzerland as well as Europe dealing with animal models studies of ADHD and prenatal stress, which enable us to bridge between the clinical and the basic research findings. Combining the clinical with the basic research together with neuropsychological and neurophysiological (EEG, fMRI) findings has a great importance in our studies of child psychiatry, since only through such an interdisciplinary research we could reach the goal of finding specific markers for early diagnosis and personalized therapy.
Our future projects are to pursue further the quest of finding biomarkers for early diagnosis for early preventive therapies. Furthermore, we continue to study mechanisms of action of drug therapy as well as specific mutation findings.
Genotyping (polymorphism and CNV). DNA RNA and protein extractions. Quantitative real-time RT-PCR. Immunohistochemistry, Cytochemistry and Western blot. Neuronal cell culture including primary cells. Lymphoblastoid culture. ELISA. Enzymatic activity assays. Life-cell imaging microscopy. xCELLigence real-time cell culture monitoring. Methylation and epigenetic analysis.
University of Zurich, Swiss National Science Foundation, Pharmaceutical industry, Alzheimer Forschung Initiative e.V.
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