Experimentelle Untersuchungen zum neuroprotektiven Einfluss von endogenem Faim2 im murinen Fadenokklusionsmodell der zerebralen Ischämie
The Influence and Neuroprotective Function of Endogenous Faim2 in the Mouse Model of Cerebral Ischemia
by Christopher Spering
Date of Examination:2014-01-07
Date of issue:2013-11-28
Advisor:Prof. Dr. Jörg B. Schulz
Referee:Prof. Dr. Jörg B. Schulz
Referee:Prof. Dr. George Trendelenburg
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Abstract
English
Apoptosis plays a major role in neurological development, differentiation and diseases. After being activated through Fas-ligands, the death receptor Fas/CD95 initiates a caspase cascade, leading to apoptosis. The activation and the signaling pathway itself have a major impact on the outcome of several neurological diseases, including cerebral ischemia. Recent studies have shown that in addition to cell death signaling, death receptors also induce proinflammatory responses and cell differentiation or proliferation. Identification of a protein, which regulates the activation of death receptors and in that function potentially influences the switch between cell death and neuroregeneration, opens new therapeutic targets. In this doctoral theses, the death receptor inhibiting molecule Fas apoptotic inhibitory molecule 2 (Faim2) was identified and characterized as an important modifyer of Fas/CD95-induced signaling, priming the apoptosis pathway. To investigate this neuron-specific and evolutionary well conserved inhibitor during development and diseases, a Faim2-deficient mouse had been generated. The lack of Faim2 causes an increase in stroke volume, neurological impairment and caspase activity in vivo as well as an increase in susceptibility to combined oxygen-glucose deprivation in primary neurons in vitro. While Faim2 was down regulated after cerebral ischemia, the expression of Fas/CD95 showed an increase, opening the discussion about alternative pathways inducing neurogenesis or neuronal branching through Fas/CD95 signaling, next to the death pathway, which leads to Apoptosis. In contrast, a lentiviral mediated overexpression of Faim2 decreased infarct volume and cell death again, completing the evidence that Faim2 is a neuroprotective molecule in the context of cerebral ischemia and potentially a therapeutic target.
Keywords: Faim2; Apoptosis; cerebral ischemia; Fas; CD95; Faim2-deficiency; caspase cascade; death receptor; neuroregeneration; neurological development; neurological disease
Schlagwörter: Faim2; Apoptose; Zerebrale Ischämie; Caspase; Fas; CD95