Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by progressive behavioral changes and/or language impairments. FTD predominantly affects the frontal and temporal lobes of the brain and is considered the most common cause of early onset dementia in people under the age of 65. Heterozygous loss of function mutations in the progranulin gene resulting in a haploinsufficiency of the protein contribute to about 30% of all familial FTD cases. Progranulin is a secreted growth factor with distinct biological roles in regulating inflammation, brain development and lysosomal function among others, with loss of progranulin being primarily associated with neurodegeneration. Despite recent advances in the understanding of progranulin-associated FTD disease mechanisms, the relative contribution of different cell types to pathogenesis is poorly characterized. Dysfunction of cell types associated with the maintenance of the blood- brain barrier such as endothelial cells were only recently found to play a central role in FTD pathophysiology. The overall objective of this proposal is to evaluate a strategy to modulate a regulatory progranulin interactor with the aim to use this interactor to upregulate progranulin protein levels endogenously and within appropriate physiological context within FTD relevant cell types. Our studies also seek for the first time to encompass the generation and characterization of an induced pluripotent stem cell-derived human neurovascular progranulin- deficiency model as a platform to identify disease relevant phenotypes. If our hypothesis is correct, increasing progranulin levels in human FTD disease-relevant cells may potentially restore a healthy control phenotype, delaying aspects of disease pathogenesis and neurodegeneration. Our studies will also design and test clinically relevant antisense oligonucleotides to boost progranulin protein levels. Since reduced progranulin levels in the brain have been linked to multiple neurodegenerative diseases beyond FTD, therapies that increase progranulin expression may also have utility for the prevention or treatment of a number of additional neurological conditions.

Loss of progranulin protein causes Frontotemporal Dementia (FTD) and increases the risk for multiple neurodegenerative diseases, including Alzheimer’s disease. Therefore, increasing progranulin expression in the brain has potential therapeutic value not only for FTD, but also for a number of other presently incurable neurological disorders. This project seeks to characterize the molecular mechanisms that underly the demise of a population of brain cells highly affected in progranulin-associated FTD and to elucidate a mechanism of endogenously modulating progranulin expression, with the aim of leveraging this mechanism to increase progranulin protein levels in FTD disease-relevant patient-derived cells.