Morphological, molecularbiological and functional characterization of neuromuscular alteratoins in diverticular disease

• Applicant: Professor Dr. Thilo Wedel
• Subject Area: Gastroenterology
• Term: from 2008 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 81528123

Diverticular disease (DD) represents one of the most common gastrointestinal diseases. Despite the high prevalence, the pathogenesis of DD, however, remains largely enigmatic. Recent evidences indicate that DD is caused by neuromuscular alterations which trigger formation of diverticula as well as symptoms. During previous funding periods, we were able to show by analyzing samples obtained from patients with diverticulitis and enteric nerve cell cultures that DD (1) is associated with a loss of enteric nerve cells (oligoneuronal hypoganglionosis); (2) displays expression deficits of the neurotrophic factor GDNF and its corresponding receptors (RET, GFRa1/2) which in turn might account for the nerve cell loss; (3) is characterized by disturbances of the serotonergic and muscarinic neurotransmitter systems which helps to explain the altered intestinal motility patterns accompanying DD, (4) displays structural and functional muscular changes further indicating an underlying neuropathy and myopathy in DD. Based on these data, the current proposal is aimed to address the following aspects: (1) To assess in patients with diverticulitis putative changes in the most important inhibitory neurotransmitter systems (NO, VIP) and whether other neurotrophic factors (GDNF family members, endothelin, neuregulin) display expression deficits. As neurotrophic factors significantly influence synaptic plasticity, markers of synaptic plasticity (synaptophysin, synaptobrevin, synaptotagmin, SNAP25) will indicate whether diverticulitis is associated with a synaptopathy. (2) The set of experiments so far carried out in patients with diverticulitis will also be conducted in patients with diverticulosis. If this collective reveals similar findings (e.g. hypoganglionosis, neurotransmitter disturbances, deficits of neurotrophic factors, synaptopathy), these data would support the hypothesis of underlying neuromuscular alterations being initially involved in the pathogenesis of DD. (3) The underlying pathomechanisms of neuromuscular changes detected in the human pathology will be further investigated in in vitro models. For this purpose, besides enteric nerve cell cultures we have established a model of cultured enteric smooth muscle cells. These in vitro models will allow to assess the influence of neurotrophic factors shown to be altered in DD on proliferation, differentiation and synaptic plasticity of enteric nerve cells as well as on structural and functional differentiation of enteric smooth muscle cells. The data obtained in the experiments proposed could revise traditional pathogenetic concepts of DD and identify enteric neuro-/myopathies as etiologic factors in DD which may allow to develop innovative concepts for prophylactic and (pharmaco-)therapeutic approaches.

• DFG Programme: Research Grants
• Participating Person: Privatdozentin Dr. Martina Böttner