"BACKGROUND:Parkinson’s Disease, characterized by the progressive degeneration of dopaminergic neurons, afflicts millions of people. Yet, no effective therapeutic strategies are available.This work uses Caenorhabditis elegans to study dopaminergic degeneration. C. elegans is a small nematode, highly amenable to genetics and high-throughput approaches, with a simple nervous system that is highly conserved at the level of gene expression and pathology with humans. This study also utilizes a mutant in a Transient Receptor Potential (TRP) channel, trp-4(d), in which dopaminergic neurons properly specify but later on progressively degenerate.OBJECTIVES:1. Understand the molecular mechanisms of dopaminergic neurodegeneration2. Identify potential therapeutic targets3. Uncover novel causes of neuronal cell deathSTRATEGIES:1. Using a candidate approach I will investigate which of the known cell death pathways (apoptosis, autophagy, necrosis) mediate trp-4(d) dopaminergic degeneration.2: I will perform a suppressor screen on trp-4(d) mutants to identify genes that can stop dopaminergic cell death. High-throughput genetic approaches (automated screening and Whole Genome Sequencing) will be employed for mutant isolation and identification. Characterization of the retrieved genes will elucidate molecular mechanisms that can block dopaminergic degeneration.3. It is conceivable that more genes exist that when mutated have, like trp-4(d), detrimental effect to the survival of DA neurons. I will take an unbiased high-throughput forward genetic screening approach designed to selectively isolate dopaminergic degeneration mutants to reveal novel causes of neuronal cell death.RELEVANCE:The expected outcomes are of high medical significance and relevance to human neurodegenerative conditions. The proposed work, employing state of the art methodology, will not only enhance European competitiveness in disease related research but also contribute to its technological excellence."