The overall goal of this research and training plan is to define the molecular mechanisms underlying tauopathies. Tau aggregates are a hallmark pathological feature of tauopathies, which include Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration and Pick's disease. While Parkinson's disease is not usually characterized as a tauopathy, a common tau gene (MAPT) haplotype is an established risk factor for disease. This project aims to define the molecular mechanisms underlying tauopathies, will improve our understanding of how tau genetics influences tau biology, and will inform novel avenues for therapeutic intervention. The investigator, Dr. Celeste Karch, will gain advanced training in stem cell biology, genomics, and axonal imaging in support of an innovative approach that establishes novel cell models that use human induced pluripotent stem cell (iPSC)-derived neurons, zinc finger nucleases, and axonal imaging to study the extent to which genetic changes in MAPT, the gene that encodes the tau protein, disrupts tau metabolism in tauopathies. The mentors, who were selected for this training, Drs. Alison Goate, Marc Diamond, Jeffrey Milbrandt, and Yadong Huang, are internationally recognized experts in the fields of human and molecular genetics, tau aggregation, axonal degeneration, and stem cell biology, respectively. The goal of this proposal is to determine how genomic variants in tau that are associated with risk for tauopathies contribute to the development of these diseases using human iPSC-derived neurons. The overarching hypothesis of this proposal is that common mechanisms exist by which disease mutations and risk haplotypes disrupt tau metabolism and contribute to disease pathogenesis. To define these common mechanisms, I will measure several modalities of tau metabolism in iPSC-derived neurons from disease mutation and risk haplotype carriers. Through this research and mentored training plan, Dr. Karch will begin to define the molecular mechanisms underlying tauopathies and will establish new experimental tools and approaches that will form the foundation for a career as an independent, translational neuroscientist.
This research and training plan will provide advanced training in stem cell biology, genomics, and axonal imaging that will support a career in cutting-edge neurodegenerative disease research. These innovative approaches will be used to define fundamental mechanisms of tau regulation and how these mechanisms are disrupted in tauopathies, which include Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, Pick's disease and corticobasal degeneration, identifying avenues for advancement in therapeutic intervention.
|Karch, Celeste M; Goate, Alison M (2015) Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77:43-51|
|Cruchaga, Carlos; Karch, Celeste M; Jin, Sheng Chih et al. (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 505:550-4|
|Jin, Sheng Chih; Benitez, Bruno A; Karch, Celeste M et al. (2014) Coding variants in TREM2 increase risk for Alzheimer's disease. Hum Mol Genet 23:5838-46|
|Karch, Celeste M; Cruchaga, Carlos; Goate, Alison M (2014) Alzheimer's disease genetics: from the bench to the clinic. Neuron 83:11-26|