Saturday, May 17, 2025
5/17/2025
Interactions between progranulin insufficiency and TDP-43 - PROJECT SUMMARY Frontotemporal Dementia (FTD) is a major cause of early onset dementia and patients can develop a wide range of symptoms including behavioral changes and language impairments. Heterozygous mutations in the progranulin gene (GRN) result in haploinsufficiency of the protein and cause FTD with TDP-43 pathology. TDP- 43 is a RNA binding protein that, in disease states, mislocalizes to the cytoplasm and forms insoluble inclusions. All FTD-GRN patients develop TDP-43 pathology, however it is not understood how partial loss of progranulin promotes TDP-43 mislocalization and aggregation. Progranulin heterozygous mice (Grn+/–) are the genetic model of FTD-GRN and develop age dependent behavioral abnormalities, but do not develop TDP-43 pathology. This project uses Grn+/– mice crossed with human TDP-43 transgenic mice (hTDP+) to investigate whether progranulin insufficiency results in TDP-43 dysregulation. Initial studies of the Grn+/–:hTDP+ mice show a severe impairment of social dominance behavior and an increase in insoluble TDP-43 in the medial prefrontal cortex (mPFC), a region critical for normal social dominance behavior. Additionally, preliminary studies suggest that there may be impairments in TDP-43-dependent splicing and autoregulation in the Grn+/–:hTDP+ mice. My overarching hypothesis is that the synergistic effects of progranulin insufficiency and TDP-43 overexpression on social dominance behaviors are due to TDP-43 dysregulation in the mPFC. This proposal will test two aims: 1) Determine if progranulin insufficiency promotes TDP-43 mislocalization and dysregulation in the mPFC and 2) Determine if impaired social dominance behaviors are driven by hTDP expression in the mPFC. As behavioral changes are a major feature of FTD, determining the role of TDP-43 in the mPFC could be vital for developing future therapeutics. The overall goal of the training plan is to instruct the PI in neurodegeneration research and provide a solid foundation for a successful career as a physician scientist. A project based in translational approaches, while focused on a disease-oriented pathogenesis, is the ideal training environment for any aspiring physician scientist. Included in the training plan are experiences that help the PI: 1) gain competence in a variety of techniques in neurobiology 2) collaborate with other scientists, 3) develop hypothesis-driven research, 4) present data in a written and oral format, 5) effectively integrate research with clinic, and 6) responsibly conduct research.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).