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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01AG046374-01
Application #
8618328
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Wise, Bradley C
Project Start
2013-12-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$113,048
Indirect Cost
$7,770
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Ferrari, Raffaele; Wang, Yunpeng; Vandrovcova, Jana et al. (2017) Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases. J Neurol Neurosurg Psychiatry 88:152-164
Ridge, Perry G; Karch, Celeste M; Hsu, Simon et al. (2017) Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience. Genome Med 9:100
Yokoyama, Jennifer S; Karch, Celeste M; Fan, Chun C et al. (2017) Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia. Acta Neuropathol 133:825-837
Wang, Chao; Ward, Michael E; Chen, Robert et al. (2017) Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening. Stem Cell Reports 9:1221-1233
Tcw, Julia; Wang, Minghui; Pimenova, Anna A et al. (2017) An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells. Stem Cell Reports 9:600-614
Karch, Celeste M; Ezerskiy, Lubov A; Bertelsen, Sarah et al. (2016) Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One 11:e0148717
Yokoyama, Jennifer S; Wang, Yunpeng; Schork, Andrew J et al. (2016) Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease. JAMA Neurol 73:691-7
Wakle-Prabagaran, Monali; Lorca, Ramón A; Ma, Xiaofeng et al. (2016) BKCa channel regulates calcium oscillations induced by alpha-2-macroglobulin in human myometrial smooth muscle cells. Proc Natl Acad Sci U S A 113:E2335-44
Karch, Celeste M; Ezerskiy, Lubov; Redaelli, Veronica et al. (2016) Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: study of pathogenetic features. Neurobiol Aging 38:215.e1-215.e12
Karch, Celeste M; Goate, Alison M (2015) Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77:43-51

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