Investigation of lithium-induced macro-autophagy in Dictyostelium. (360G-Wellcome-085811_Z_08_Z)
We will investigate the molecular mechanism by which lithium (Li+) induces macro-autophagy and promotes clearance of protein aggregates. Our investigation will use a combination of genetics and cellular pharmacology to study induction of macro-autophagy and protein clearance in the social amoeba Dictyostelium. These studies will draw on our previous work on the cell biological effects of Li+ and the genetics of lithium sensitivity. We will monitor induction of macro-autophagy by use of ATG8- GFP, a fluorescent marker for autophagosome formation in living cells, and follow clearance of protein aggregates, using expression of fragments of human Huntingtin. We will examine the dose-response to Li+, and specific derivatives of VPA, and investigate their behaviour in combination with rapamycin, a mTOR inhibitor. The major component of this project will use Dictyostelium genetics to examine: i) which inostiol phosphate (IP3 or PIP3) is the immediate lithium target; ii) where in the pathway lithium interacts with autophagy regulatory (atg) genes; iii) our collection of mutants with altered lithium sensitivity to identify new components of the pathway that connects inositol phosphate signalling to regulation of autophagy. These results should inform the design and implementation of a general pharmacological therapeutic approach for the treatment of protein aggregation diseases.
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Grant Details
Amount Awarded | 161345 |
Applicant Surname | Harwood |
Approval Committee | Molecules, Genes and Cells Funding Committee |
Award Date | 2008-07-10T00:00:00+00:00 |
Financial Year | 2007/08 |
Grant Programme: Title | Project Grant |
Internal ID | 085811/Z/08/Z |
Lead Applicant | Prof Adrian Harwood |
Partnership Value | 161345 |
Planned Dates: End Date | 2012-01-31T00:00:00+00:00 |
Planned Dates: Start Date | 2009-02-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | Wales |