Developing mouse models of FTD due to progranulin deficiency
University of British Columbia
Mutations (genetic mistakes) in a gene that makes a protein called progranulin are an important cause of a very specific form of age-related brain degeneration called Frontotemporal Dementia (FTD). Mutations in the progranulin gene are thought to cause FTD due to a loss of progranulin function. The development of new mouse models that allow us to study the function of the progranulin protein will provide critical information about progranulin’s role in the brain. Treatments that increase progranulin expression or function are being developed. In order to test treatments that might increase progranulin levels or function, we will need laboratory models in which to test these treatments.The primary goal of this proposal is to generate mouse models that will allow us to address this critical un-met need in the field, and will accelerate therapeutic development for FTD. SPECIFIC AIM: To develop mice that can be used to study the function of the human progranulin gene.
Specifically, we will develop and study mice that express both normal and mutant human progranulin and will also examine the effect of the human progranulin in these mice in the absence of mouse progranulin.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Appropriate model systems in which to study disease-targeting treatments are highly valuable (but often lacking) prerequisites for clinical trials in CNS disorders. Given the high cost of human clinical trials for brain diseases such as FTD, these studies should be preceded by comprehensive preclinical assessments. Mouse models expressing human progranulin will significantly accelerate the development of progranulin-modulating therapies. These mice will be useful for 1) measuring changes in human progranulin in response to therapeutics, 2) measuring changes in brain levels of GRN and correlating those changes with changes in more clinically feasible peripheral GRN levels or other biomarkers, and 3) evaluating potential off-target effects associated with altering systemic GRN levels.
In this proposal we will develop several novel mouse models using state-of-the-art methods. These mice will help us to understand progranulin function and regulation in the brain. To our knowledge, there are currently no mouse models expressing human progranulin available for study. This proposal will generate and characterize mice expressing both wild-type and mutant forms of human progranulin and also look at this in the absence of mouse progranulin. The use of this type of mouse model often reveals differences between disease-related human proteins and the equivalent mouse proteins. We will be the first to address this possibility with respect to the important brain disease-related protein progranulin.