Necrotic cell death underlies the pathology of numerous human neurodegenerative disorders. However, contrary to the remarkable progress in deciphering the biochemistry of apoptosis, little is known about the molecular mechanisms that bring about necrotic c ell death. Although mitochondria play an essential role in apoptosis, their involvement in necrosis is poorly understood. This project aims at elucidating the mitochondrial pathways involved in the regulation and proper execution of necrosis, using C. eleg ans as a model organism. Degenerative cell death of motor neurons and other nerve cells of C. elegans can easily be triggered by genetic manipulations and environmental factors. This provides the essential tools required to determine the molecular mechanis ms by which mitochondria participate in necrosis in this simple and powerful animal genetic system. To achieve this goal, we will (1) implement optical imaging methods to analyse mitochondrial structure and function in dying neurons, (2) screen the C. eleg ans genome for genes involved in mitochondrial processes essential for necrosis, analyse the function of the identified genes, and (3) delineate the mitochondrial molecular pathways responsible for necrosis in C. elegans. Dissection of the molecular mechan isms that govern mitochondrial involvement in necrosis will offer insights into disease and pathogenesis and in due course, provide novel targets for therapeutics. As such, deciphering the mitochondrial role in necrosis is of fundamental importance towards the development of educated strategies aiming to combat diseases of the nervous system, which is a priority of the Sixth Framework Programme. The proposed investigation uniquely merges the applicant¿s experience on mitochondrial research with the expertis e of the Host Institution in necrotic cell death in C. elegans. Such blending will greatly facilitate the development and transfer of research competencies, contributing to enhance EU scientific excellence.
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