Genetic and environmental modulation of necrosis and health span in Caenorhabditis elegans

Living systems rely on tightly regulated gene expression networks in order to maintain a stable internal milieu, a process known as homeostasis, and to interact with their environment. The study of regulatory networks involved in key processes such as energy metabolism and cellular responses to hostile environmental conditions has immense therapeutic potential and is the focus of a large and growing body of research. This dissertation describes two processes – neuronal necrosis, and the metabolic effects of the phytoecdysteroid 20-hydroxyecdysone in the invertebrate model system C. elegans, with a focus on the underlying molecular mechanisms and their potential therapeutic value. The first part of this dissertation deals with the cellular response to necrosis, a catastrophic event caused by extreme departure from homeostatic conditions due to exposure to toxic chemicals, extreme temperature or mechanical trauma. Using genetically encoded hyperactive DEG/ENaC ion channels as inducers of necrosis, I describe the role of ER chaperone NRA-2 in the modulation of necrosis caused by calcium excitotoxicity and suggest a broader role for ER chaperones in the regulation of channel expression, with potential therapeutic value in the treatment of disease pathology caused by malformed DEG/ENaC channels. The second part of this dissertation deals with the effects of the plant-derived steroid hormone 20-hydroxyecdysone (20HE) that extends C. elegans health span and modulates energy metabolism. I describe the effects of this compound on conserved metabolic pathways and suggest a potential mechanism of action. This study highlights the conservation of gene networks governing nutrient metabolism and the importance of C. elegans as a model system in identifying therapeutic targets for the treatment of metabolic syndrome. In sum, the dissertation describes two unrelated processes in C. elegans with the common theme being a conserved genetically encoded regulatory network and its interaction with a specific environmental cue.Ph.D.Includes bibliographical referencesby Shaunak Kama