Frontotemporal dementia (FTD) is a devastating neurodegenerative disease affecting behavior and memory. It is the second most common cause of dementia in persons under the age of 65. Recently, mutations in the progranulin gene (GRN) were discovered to cause tau-negative, ubiquitin-positive cases of FTD (1-5). GRN is a mitogenic growth factor expressed by epithelial cells that stimulates proliferation. It is expressed in skin, Gl tract, reproductive tissues, and in the central nervous system, including subsets of neurons and microglia (6). Little is known about the biology of progranulin in the brain. Human mutations in the progranulin gene that lead to FTD appear to result in haplosufficiency for the gene product, suggesting that insufficiency of a signaling pathway may be pathogenic (1-5). Currently, there are no animal models of progranulin-deficient FTD. My goal is to elucidate whether progranulin is a protective factor that promotes neuronal survival in response to cellular stress using in vitro and in vivo models of Grn-deficiency. The determination of progranulin's function in the CNS will shed light on pathways that may be misregulated in FTD. I hypothesize that Grn-deficienct mice will recapitulate many features of human FTD. If this is the case, the mice can be utilized for a multitude of studies including cell biology, disease mechanism studies, genetic studies to identify modifier genes, and pharmacological studies to test newly developed therapies.
Aim 1. Determine if progranulin is required for preserving neuronal function in response to cellular stress.
Aim la. Determine if progranulin is necessary for neuronal function in response to cellular stress in vitro.
Aim lb. Determine if cellular stress is sufficient to induce TDP-43 aggregation in progranulin deficient neurons in vitro.
Aim 2. Determine if mice lacking progranulin will develop neurodegeneration with aging. Age is the major risk factor for most neurodegenerative diseases, including frontotemporal dementia. As human lifespan continues to increase more individuals will be affected by neurodegeneration. It is imperative to begin to understand disease pathogenesis in order to find ways to treats and prevent disease. Elucidating the normal function of progranulin in the CNS using a knockout mouse model is a first step.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F01-E (20))
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Snyder, Stephen D
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Minami, S Sakura; Min, Sang-Won; Krabbe, Grietje et al. (2014) Progranulin protects against amyloid ? deposition and toxicity in Alzheimer's disease mouse models. Nat Med 20:1157-64
Filiano, Anthony J; Martens, Lauren Herl; Young, Allen H et al. (2013) Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice. J Neurosci 33:5352-61
Rosen, Ezra Y; Wexler, Eric M; Versano, Revital et al. (2011) Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling. Neuron 71:1030-42