We are currently looking for enthusiastic PhD students to join us in 2011. Projects are available in any of the research topics described in our research pages, but especially in the three areas described here. For application details see our PhD opportunities page and the Department of Zoology web pages.
Suggested Projects
How do presenilins control neuronal function and calcium signalling?
How does IP3 signalling regulate sensitivity to RNAi?
The mechanisms of signal specificity in polymodal neurones
How do presenilins control neuronal function and calcium signalling?
Mutations in presenilin genes are the most common cause of inherited Alzheimer’s disease. We use C. elegans to answer fundamental questions about the role of presenilins.
Neuronal function. We have shown that mutations in presenilins cause changes in synaptic function, an observation that has also been made in mammals. However the mechanisms underlying this change and its importance to Alzheimer’s disease remain unclear. You will use a combination of genetic, transgenic, molecular and physiological approaches to dissect the mechanisms by which presenilins control synaptic function. To do this you will look for new genes involved in this process using RNAi or genetic screens and also test interactions between presenilins and proteins known to be involved in synaptic function. You will assay neuronal function using physiological approaches (e.g. calcium imaging) and behavioural assays. Our aim is to gain new insights into how presenilins regulate synaptic function and thus how presenilin dysfunction may alter the behaviour of the nervous system.
Calcium signalling. Presenilin mutations are known to cause changes in calcium signalling and we have shown that this is also true in C. elegans. However the mechanism by which this occurs is unclear although it is clear that IP3 signalling is important. You will test different models for the action of presenilins on calcium signalling using a combination of transgenic, genetic and molecular approaches. In particular you will introduce a range of mutant presenilins with known changes in protein behaviour into worms and test their effect. The project will focus on the role of this interaction in the nervous system and will use a combination of calcium imaging and behavioural assays to measure function.
Other projects in this research area are also available.
How does IP3 signalling regulate sensitivity to RNAi?
RNA interference (RNAi) is a widespread phenomenon in animals, in some organisms RNAi is systemic, that is, it spreads between cells. Further RNAi may be environmental so that it can be induced by the RNA taken up from the animal’s environment. The widely used model organism C. elegans is a notable example of an animal in which these processes occur. We have discovered that C. elegans mutants with defects in the IP3 signalling pathway are hypersensitive to RNAi. Intracellular signalling through IP3 (inositol 1,4,5-trisphosphate) acts through calcium to control the physiology and behaviour of animals in response to changes in their environment and physiology. This is the first time that a signalling pathway, such as this, has been implicated in determining the sensitivity of animals to RNAi and it raises important questions about the control of RNAi sensitivity in response to external conditions.
You will address the mechanism by which this pathway works. We wish to address two fundamental questions: How does IP3 signalling control RNAi sensitivity and what are the signals that regulate IP3 signalling in this process? To address these questions you will use a combination of genetic, transgenic and molecular approaches together with behavioural assays to identify other components of these mechanisms and thus address the fundamental questions described above.
The mechanisms of signal specificity in polymodal neurones
Many sensory neurones (e.g. pain nociceptors) are polymodal; that is they respond to a range of different stimuli. How they respond to and transduce information about specific stimuli is unclear. We have shown that in the ASH neurones of C. elegans IP3 and Ca2+ signalling are important to two specific responses. We now wish to further dissect these signalling pathways and to test the hypothesis that one of them is a novel signalling pathway. The project will use molecular, transgenic and genetic approaches combined with behavioural tests of ASH function and calcium imaging of the ASH neurones.