Healthy organismal ageing: Identification and mechanistic characterisation of modifiers of transcellular stress signalling.
Dr Patricija van Oosten-Hawle
Prof I A Hope
Applications accepted all year round
Self-Funded PhD Students Only
The regulation of stress response mechanisms that maintain cellular proteostasis have been historically investigated in isolated tissue culture cells and unicellular organisms. Therefore, regulation of proteostasis is understood in a strict cell-autonomous manner, regardless of the health state of neighbouring cells. However recent evidence in different multicellular model systems, including C. elegans has shown that cellular stress responses are organized coordinately between and across tissues by transcellular chaperone signalling in metazoans. For example an imbalance of proteostasis within one tissue is sensed and signalled to other tissues within the organism to adjust chaperone levels, minimize the risk of proteotoxic damage and increase survival and lifespan.
This project is designed to identify components required for transcellular stress signaling between tissues, using C.elegans a model system. This will be accomplished by genetic screens using fluorescent transcellular stress gene reporters, that respond to local proteotoxic stress by increased stress gene reporter expression in several receiving tissues. In order to identify genes that are required for the proper transmission of the response, reporter strains will be chemically mutagenized and screened for reduced expression of the fluorescent reporter. Mutant genes will be identified using whole-genome sequencing and studied mechanistically to understand their role in transcellular signal transmission and rate of aging in the organism.
The discovery of transcellular stress signaling has led to the realisation that protein quality control is regulated across cellular boundaries to achieve organismal proteostasis. Damaged and misfolded proteins accumulate during aging and seem to have a causative role in tissue decline and diseases that characterize old age. The project is designed to understand the genetic and molecular mechanisms that regulate aging and age-onset protein misfolding diseases in a multicellular organism. In particular, it aims to provide new insight into how age-dependent protein folding stress is communicated between different tissues and organs and why an organism loses control over tissue-specific protein quality control mechanisms and protective stress responses. Defining the mechanisms regulating organismal proteostasis throughout the lifespan of an animal, will provide strategies for future avenues for age-dependent disease treatments.
Please see following links for more information:
We are looking for highly motivated candidates with a passion and curiosity to understand the mechanisms of protein quality control in an intact organism, that will allow to find treatments for aging and neurodegenerative diseases.
van Oosten-Hawle P., Porter, R.S., Morimoto, R.I., Cell (2013); 153(6): 1366-78.
Craig, H et al., (2013) BMC Genomics, 14; 249.
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