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Analysing Intravital Neuronal Protein Interactions in Metabolism and Apoptosis

Final Report Summary - AINIGMA (Analysing Intravital Neuronal Protein Interactions in Metabolism and Apoptosis)

The brain consumes a large proportion of the body’s energy production for its normal function. Therefore, it is very vulnerable to a variety of diseases if energy supplies are interrupted. Neurons are particularly intolerant of inadequate energy supply and die or degenerate in an acutely or chronically disturbed metabolic environment, such as after stroke. The goal of this research project was to characterize a way how cell death pathways in the brain intersect with pathways regulating metabolism and how these essential pathways regulate neuronal degeneration in stroke.
Since the beginning of the project, the fellow has carried out research on the basic molecular mechanisms of these pathways. During the first phase of the project, a focus of the work was placed on developing and refining methods to apply high-content microscopy-based and time-resolved fluorescence microscopy methods that are well established in the laboratory of the outgoing host to work with neuronal culture systems, both employing primary rodent and human induced pluripotent stem cell-derived neurons. Furthermore, a focus was placed on obtaining proof-of-concept data for the feasibility of demonstrating high-content microscopy-based functionality of small-molecule protein:protein interaction inhibitors designed according to specific molecular mechanisms. In addition, generation of expression systems for protein:protein interaction studies in live mammalian cells for further regulatory pathway analysis have been performed. In the second phase of the project, chemical biology tools have been employed to provide mechanistic insight, and time-resolved fluorescence microscopy was used to analyze specific molecular events in neuronal cell death regulation.
This project addressed the pressing need to develop novel treatment approaches for acute neurodegeneration in stroke, but it also extends and relates to Alzheimer’s disease and other forms of dementia by investigating molecular pathways common to the different pathophysiology of these diseases. Increased life expectancy in Canada, the country of the outgoing host, as well as in the European Union will further contribute to a constant rise in these diseases. Thus, by investigating the pathophysiological basis for acute and chronic neurodegeneration, this project contributed to mitigating the future challenges imposed by the care for Canadian and European patients suffering from these diseases.