Summary
This project investigates the molecular mechanisms of progranulin's neurotrophic effects in frontotemporal dementia (FTD) caused by GRN mutations, hypothesizing that progranulin acts in lysosomes to maintain thalamocortical circuitry and correct FTD-related social deficits and pathology.
What they want
The research aims to determine if progranulin promotes dendritic arborization by enhancing cathepsin activity, if progranulin acts in lysosomes to maintain FTD-related thalamocortical circuitry, and if selectively boosting lysosomal progranulin will correct FTD-related social deficits and pathology. These aims will be tested using primary cortical neurons and mouse models, including a novel Grn+/–:TDP-43 transgenic mouse cross, to advance understanding of FTD-GRN pathogenesis and inform the design of progranulin-boosting therapies.
Deliverables
- Advance understanding of FTD-GRN pathogenesis
- Provide insight into FTD-TDP and Alzheimer’s disease (AD)
- Inform design of progranulin-boosting therapies
- Reveal lysosomes as progranulin’s key site of action
- Potential for a new treatment strategy for FTD via selective lysosomal progranulin delivery
Technical requirements
- Use of lysosome-targeted progranulin (L-PGRN) viral vector
- Studies in primary cortical neurons
- Use of Grn+/– mice
- Use of a novel Grn+/–:TDP-43 transgenic mouse cross
- Assessment of dendritic arborization
- Assessment of cathepsin activity
- Assessment of MDt-mPFC connectivity
- Assessment of FTD-related social deficits and pathology
