The role of actin in cell homeostasis

Cells of all organisms receive signals that must be responded to. It is important for cells to co-ordinate different signalling pathways so they can perform their correct functions. Research in my laboratory uses a simple one-celled organism as a model system. Many processes are known to happen in the same way in this cell-type and in cells of more complex organisms such as mammals. We are particularly interested in the function of one protein called actin. Actin is part of a structure called the cytoskeleton (meaning cell skeleton) that helps give a cell its shape. Unlike a human skeleton however, actin is dynamic and constantly rearranging. We propose that this dynamic quality allows actin to act as a sensor of the cell environment to assess energy levels and whether the cell is under stress. If the environment is good, then cell processes can go ahead. If actin cannot function due to low energy or because it is modified by oxidants it can cause cells to enter a cell death pathway. While this is a fundamental cell biology problem, knowing how cells respond to stress impacts on our understanding of ageing and on disorders including neurodegeneration and cancer.

The overall aims of my proposed research are to further our understanding of the role of actin in cells, and to determine how it functions to integrate essential processes to ensure cell survival or to trigger cell death.
Specifically, the research programme will-
-increase understanding of the mechanistic role of actin during endocyosis and determine how this interfaces with the specific cargo binding role of the Sla1 protein
-determine how the Gts1 protein that localises with actin patches in cells is able to control cell oscillations that are critical for co-ordinating temporal aspects of cell organisation
-determine how modifications in actin perturb its behaviour and lead to disease, ageing and cell death.
The proposed research is organised into three main areas as outlined by the objectives, and is based on results (mostly published) from studies conducted during my current fellowship. My previous studies and those from a number of other scientists incuding the Nobel Prize winner Paul Nurse, have shown that a relatively simple organism such as yeast can be extremely informative about fundamental cell processes. We will continue to exploit the genetic and proteomic advantages of budding yeast in these studies. In addition, I will initiate collaborative studies to increase use of mammalian tissue-culture cells and also developmental model systems in order to exploit our findings from yeast in directed studies on cells from more complex eukaryotes. One of the central methodologies that is used within my research is intracellular imaging and study of dynamics of cellular processes. This is one of the MRC current planning priorities and will continue to be an area of active study and development for the lab.
It is expected that a significant number of publications will arise from the proposed research and I will aim to publish in journals of high impact and repute in the field. I will also present my research at national and international meetings in order to disseminate our findings at a number of levels. The research will generate a number of new tools including strains and plasmids, as well as improved methodologies for certain assays. These will be sent, or communicated, to relevant individuals. While the research does not directly target therapeutics for specific diseases, knowledge gained from the programme could impact on research into sickle cell disease (actin modification) and neurodegenerative diseases (defects in endocytosis have been linked to Huntingdon‘s disease and early stage Alzheimers).