Our major research focus comprises the genetics of complex diseases such as neurogastroenterologic disorders and (comorbid) neuropsychiatric conditions. In order to nail down disease relevant genes, we are performing gene sequencing/genotyping followed by association studies in irritable bowel syndrome (IBS) as well as comorbid conditions such as anxiety and depression. Most recently, we started working on the complex genetics of Hirschsprung’s disease (HSCR), a neurodevelopmental disorder of the enteric nervous system (ENS). Here we are following up a trio based approach to identify novel HSCR related genes. Identified candidates will further be explored regarding their causative relevance applying a complementing analysis pipeline including comparative expression analysis in man and mouse, gene knock down/ editing, and morphological and functional in vitro analyses (Figure 1).
|Figure 1 Research pipeline AG Niesler|
In order to better understand changes in enteric neuronal function we have established human and murine enteric progenitor cell models. The enteric neuron-like cells are currently functionally analysed by our collaborators using MSORT (Multiple site optical recording technology) and electrophysiology. The neurodevelopmental cell model is aimed to be manipulated by miRNAs/siRNAs as well as genome editing using CRISPR/Cas to get an idea about the functional relevance of candidate genes in ENS development and function (proliferation capacity, apoptosis, migration, neuronal differentiation capacity etc.). This will be complemented by exposition studies applying relevant stressors in the pathogenesis of neurogastroenterologic disorders like stress, inflammation and will enable monitoring changes before/after intervention.
Figure 2 Multiple layers of complexity in the pathogenesis of the neurogastroenterologic disorder IBS and comorbid conditions (Review COST Action BM1106 GENIEUR: Gazouli et al. 2016)
The crucial role of environmental factors in the pathoaetiology of IBS and comorbid conditions besides genetic factors is well established (Figure 2). However, environmental factors such as stress, trauma, and infection and in particular nutrition and allergens have largely been neglected in the past. The interplay between the environment and the genetic background shaping the individual epigenetics of a patient has only been poorly addressed to date. Therefore, I spent my efforts during the last years in networking to establish a research environment in which these factors will be assessed in a harmonised manner and complementarily analysed on pan-European level in a multidisciplinary team:
With the support of the COST programme (Cooperation in Science and Technology), we established in 2011 the COST Action BM1106 GENIEUR (The Genes in Irritable Bowel Syndrome Research Network Europe, GENIEUR.eu). The major goal of GENIEUR comprised the definition of a harmonised patient and control recruitment scheme as well as the establishment of a European biobank to investigate factors contributing to IBS on different levels (genomics, epigenomics, microbiomics, metagenomics). Our long term goal, is to dissect the molecular pathogenesis of IBS and its comorbidities as well as the establishment of an evidence-based diagnostics and therapeutics
Most recently, the H2020 consortium DISCOvERIE - Development, dIagnosis and prevention of gender-related Somatic and mental COmorbiditiEs in iRritable Bowel Syndrome In Europe (discoverie.eu) kicked off. DISCOvERIE aspires to advance in the understanding of causative mechanisms of most frequent and demanding mental and somatic comorbid conditions affecting IBS, by focusing on microbiome, intestinal permeability, central nervous system processing, neuroinflammation and specific genomic/epigenomic marks to define patient subgroups for improved diagnostics and therapy.