An integrative approach to understanding effects of valproate in C. elegans

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Munasinghe, Dona Helani (2015). An integrative approach to understanding effects of valproate in C. elegans. University of Birmingham. Ph.D.

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Abstract

Obesity is one of the biggest public health problems today, leading to type II diabetes, coronary heart disease, hypertension, sterility and cancer (Hashmi et al., 2013). \(C.elegans\) has been used extensively in obesity research to dissect the underlying principles. The overarching goal of my thesis has been to identify molecular signatures linking phenotypic and molecular responses of the nematode \(C.elegans\) to a number of experimental conditions that induce alteration in lipid metabolism. More specifically, I developed experimental procedures in \(C.elegans\) to study the effects of exercise, diet and a \(C.elegans\) antiageing drug valproate. Using a modified lipid assay, I found for the first time that valproate induce lipid accumulation in \(C.elegans\) in a dose dependent manner. In this study obesity is induced in \(C.elegans\) by treating with either cholesterol or sodium valproate. Using microarray technology, expression profiles associated with the induction of obesity are studied. In addition, \(C.elegans\) were treated with monosodium glutamate which is found to decrease lipid mass. Exercise is a recommendation for obese people and hence a \(C.elegans\) model system is developed to study effect of exercise. Effects of valproate on \(C.elegans\) with respect to lipid quantity are studied in detail, with emphasis on insulin signalling pathway. Expression changes associated with insulin mutants are compared with the valproate exposure expression profile to understand how much of the valproate exposure could be explained by insulin signalling. I also found for the first time that valproate cause a global down regulation of nuclear components. A hypothesis on lipid accumulation on valproate exposure is presented. TGF-β pathway is also found to be involved in fat metabolism. Finally I report an interesting phenotype for the first time in which the TGF-β pathway receptor mutant \(sma\)-\(6\) shows paralysis in response to valproate.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):