Grant: Operating Grant

Much has already been learned from established mouse models of frontotemporal dementia (FTD) that are known to be caused by mutation of the MAPT gene, the first genetic form of FTD identified. In 2006, mutations were identified in the Progranulin gene (PGRN) that cause a common type of familial FTD associated with a specific pattern of protein aggregation in the brain (FTLD-U). These PGRN mutations result in significantly decreased levels of progranulin protein which appears to be an important growth factor for brain cells (neurons). My laboratory has an established track record of excellence in both experimental therapeutics, neurogenetics, and the generation of genetically-modified mouse models of human neurologic disease. We will examine the effects of modulating progranulin levels in cell culture systems and in the whole mouse brain. We have developed a mouse model of human FTLD-U by producing mice that can be selectively induced to lack the PGRN gene that makes progranulin in specific cells or at specific times in development. These mice represent the first established conditionally-targeted PGRN animal, are a critical tool to study the function of progranulin in the brain, and may be a model of this common type of hereditary dementia. The development of such a model will be crucial for future studies examining how the loss of progranulin causes the dysfunction and death of neurons in FTD, and for the eventual development of treatments for this devastating disease.