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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
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Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Wise, Bradley C
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Washington University
Schools of Medicine
Saint Louis
United States
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Karch, Celeste M; Hernández, Damián; Wang, Jen-Chyong et al. (2018) Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network. Alzheimers Res Ther 10:69
Bonham, Luke W; Karch, Celeste M; Fan, Chun C et al. (2018) CXCR4 involvement in neurodegenerative diseases. Transl Psychiatry 8:73
Broce, Iris J; Tan, Chin Hong; Fan, Chun Chieh et al. (2018) Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. Acta Neuropathol :
Hsu, Simon; Gordon, Brian A; Hornbeck, Russ et al. (2018) Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther 10:67
Li, Zeran; Del-Aguila, Jorge L; Dube, Umber et al. (2018) Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure. Genome Med 10:43
Tan, Chin Hong; Fan, Chun Chieh; Mormino, Elizabeth C et al. (2018) Polygenic hazard score: an enrichment marker for Alzheimer's associated amyloid and tau deposition. Acta Neuropathol 135:85-93
Li, Yi; Barkovich, Matthew J; Karch, Celeste M et al. (2018) Regionally specific TSC1 and TSC2 gene expression in tuberous sclerosis complex. Sci Rep 8:13373
Sato, Chihiro; Barthélemy, Nicolas R; Mawuenyega, Kwasi G et al. (2018) Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 98:861-864
Karch, Celeste M; Wen, Natalie; Fan, Chun C et al. (2018) Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum. JAMA Neurol 75:860-875
Sato, Chihiro; Barthélemy, Nicolas R; Mawuenyega, Kwasi G et al. (2018) Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 97:1284-1298.e7

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