Dr. Timothy Miller, MD, PhD is an excellently trained, physician scientist with a long standing interest in aging and neurodegenerative disorders. He has recently started as an Assistant Professor in Neurology at Washington University and is now seeking support for further mentorship as he focuses on a novel treatment strategy for Alzheimer's disease and Frontotemporal dementia. Building on prior experience using antisense oligonucleotides to down regulate genes in the brain and spinal cord, Dr. Miller is now using a similar strategy to either decrease overall levels of tau or decrease the 4R:3R tau ratio by changing exon splicing. He will test whether these changes in tau affect behavioral and pathological phenotype in amyloid beta depositing mice or the N279K tau mutation mice. His short term goals are to launch an academic career, expand a small translational research group, obtain independent funding (RO1), and to gain experience with understanding and treating Alzheimer's and Frontotemporal dementia mouse models. Dr. Miller's long term goal is to develop a moderate sized, exciting, research group with real impact on the understanding and treatment of neurodegenerative diseases of aging. To accomplish these goals, he has enlisted two outstanding, experienced researchers in aging research as mentors, David Holtzman and Alison Goate. His career development plan includes frequent meetings with these mentors, attendance and presentation at neurodegeneration focused seminars, attending a Neurobiology of Disease Course, attending a Designing clinical outcomes course, frequently reviewing pathology, especially tau-focused pathology, gaining experience with mouse cognitive behavioral analyses, and completing an Ethics and Research science course. Washington University School of Medicine has an outstanding track record of mentorship, in particular with K awardees and has multiple labs focused on neurodegenerative disorders. This will provide a rich and supportive scientific environment for mentorship in aging research. Dr. Miller has ample (800sq feet) laboratory space and equipment to accomplish this research project.

Public Health Relevance

There are no treatments which substantially delay the progression of Alzheimer's disease or Frontotemporal dementia. This application tests whether changing the amount or the particular form of a protein called tau will improve behavior and pathological changes in mouse models of Alzheimer's disease and Frontotemporal dementia. This novel therapeutic strategy, if successful, would be applicable to treating human dementias.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS074194-02
Application #
8144917
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (A1))
Program Officer
Sutherland, Margaret L
Project Start
2010-09-30
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$182,667
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
DeVos, Sarah L; Miller, Rebecca L; Schoch, Kathleen M et al. (2017) Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med 9:
Hoye, Mariah L; Koval, Erica D; Wegener, Amy J et al. (2017) MicroRNA Profiling Reveals Marker of Motor Neuron Disease in ALS Models. J Neurosci 37:5574-5586
Schoch, Kathleen M; DeVos, Sarah L; Miller, Rebecca L et al. (2016) Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model. Neuron 90:941-7
Koval, Erica D; Shaner, Carey; Zhang, Peter et al. (2013) Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum Mol Genet 22:4127-35
Winer, Leah; Srinivasan, Dushyanth; Chun, Seung et al. (2013) SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy. JAMA Neurol 70:201-7
Crisp, Matthew J; Beckett, Jeffrey; Coates, Joan R et al. (2013) Canine degenerative myelopathy: biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model. Exp Neurol 248:1-9
Holmes, Brandon B; DeVos, Sarah L; Kfoury, Najla et al. (2013) Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A 110:E3138-47
DeVos, Sarah L; Miller, Timothy M (2013) Direct intraventricular delivery of drugs to the rodent central nervous system. J Vis Exp :e50326
Miller, Timothy M; Pestronk, Alan; David, William et al. (2013) An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 12:435-42
DeVos, Sarah L; Goncharoff, Dustin K; Chen, Guo et al. (2013) Antisense reduction of tau in adult mice protects against seizures. J Neurosci 33:12887-97

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