2007 Pilot Projects
Descriptions and progress of each award can be found in the project details.
Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty click on their names below.
Misfolded protein accumulation and neurodegeneration due to phospholipase gene mutations
Principal Investigator: Paul Kotzbauer (WashU Neurology)
Co-investigator: B. Joy Snider (WashU Neurology)
Many neurodegenerative disorders are defined by accumulations of misfolded proteins in the brain. Mutations in the gene PLA2G6, which is involved in lipid metabolism, lead to neurodegenerative disorders and accumulation of alpha-synuclein — the same protein that accumulates in the brains of Parkinson’s Disease patients. This project will develop methods to detect misfolded protein accumulation in cultured neurons, and will generate a new animal model of alpha-synuclein overproduction. These new tools will enable the development of therapies to minimize toxicity and improve clearance of misfolded proteins.
Li M., Husic N., Lin Y., Christensen H., Malik I., McIver S., Daniels C.M., Harris D.A., Kotzbauer P.T., Goldberg M.P., Snider B.J. Optimal promoter usage for lentiviral vector-mediated transduction of cultured central nervous system cells. Journal of Neuroscience Methods 189(1):56-64, (2010).
Dhavale DD, Tsai C, Bagchi DP, Engel LA, Sarezky J, Kotzbauer PT. A sensitive assay reveals structural requirements for α-synuclein fibril growth. J Biol Chem.;292(22):9034-9050, (2017).
Updated January 2019
Function of FGF14 in progressive spinocerebellar ataxia
Principal Investigator: David Ornitz (WashU Developmental Biology)
Co-investigators: Kel Yamada (formerly WashU Neurology), Jeanne Nerbonne (WashU Developmental Biology), David Wozniak (WashU Psychiatry)
Patients with spinocerebellar ataxias (SCAs) experience a loss of muscle control in their arms and legs, with resulting loss of balance and coordination. Patients with SCA type 27, a dominantly-inherited condition, have progressive ataxia as well as mental retardation. SCA27 is caused by a single-gene mutation in the gene encoding fibroblast growth factor 14 (FGF14). An animal model lacking FGF14 function shows similar behavior. This project will fully characterize the degenerative phenotype in FGF14-deficient animals. Additionally, these investigators will generate an animal model which more closely resembles the genetics of the human disease, to reveal the molecular mechanisms which lead from FGF14 mutation to degeneration of cerebellar neurons.
Grants and Awards
“FGF14 in the regulation of Purkinje neuron excitability and SCA27“
NIH-NINDS, R01NS065761-01 (PI, Ornitz)
The molecular, cellular and physiological studies proposed will provide new and fundamentally important insights into the functional roles of FGF14 in regulating neuronal excitability and into the underlying molecular mechanisms by which mutations in FGF14 cause disease in humans.
FGF14 mutant mouse, SCA27
Laezza, F., Lampert, A., Kozel, M.A., Gerber, B.R., Rush, A.M., Nerbonne, J.M., Waxman, S.G., Dib-Hajj, S.D., and Ornitz, D.M. FGF14 N-Terminal Splice Variants Differentially Modulate Nav1.2 and Nav1.6-Encoded Sodium Channels. Mol Cell Neurosci 42, 90-101, (2009).
Shakkottai, V.G., Xiao, M., Xu, L., Wong, M., Nerbonne, J.M., Ornitz, D.M., and Yamada, K.A. FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons. Neurobiol Dis 33, 81-88, (2009).
Xiao, M., Bosch, M.K., Nerbonne, J.M., and Ornitz, D.M. FGF14 localization and organization of the axon initial segment. Mol Cell Neurosci 56, 393-403, (2013).
Bosch MK, Nerbonne JM, Ornitz DM. Dual transgene expression in murine cerebellar Purkinje neurons by viral transduction in vivo. PLoS One. 9(8):e104062, (2014).
Bosch MK, Carrasquillo Y, Ransdell JL, Kanakamedala A, Ornitz DM, Nerbonne JM. Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance. J Neurosci.; 35(17):6752-69, (2015).
Bosch MK, Nerbonne JM, Townsend RR, Miyazaki H, Nukina N, Ornitz DM, Marionneau C. Proteomic analysis of native cerebellar iFGF14 complexes. Channels (Austin, Tex).;10(4):297-312, (2016).
Updated June 2017
Microdevice development for the study of axon degeneration and injury
Principal Investigator: Shelly Sakiyama-Elbert, PhD (formerly WashU Biomedical Engineering)
Co-investigators: Karen O’Malley (WashU Neuroscience), Amy Shen (formerly WashU Mechanical Engineering)
The axon of a nerve cell functions like a highway, shuttling neuronal components that are necessary for the nerve cell’s survival. An emerging idea in degenerative disorders is that a loss of axon function plays an important role in the initiation and progression of diseases such as in Alzheimer’s, Parkinson’s, or ALS. The overall goal of this research is to design and use compartmented chambers to allow the study of axon growth and function under controlled conditions. These microdevices will allow precisely controlled delivery of drugs or toxins to examine their effects on axon function. Through these studies we will gain a better understanding of factors that contribute to neurodegenerative disorders, and test potential drugs under controlled conditions to determine their effectiveness.
Grants and Awards
“Axon Targeted Microdevices for CNS Axon Transport Studies”
NIH-NINDS, R21NS067561-01 (PI, Sakiyama-Elbert)
The goal of this project is to develop novel microdevices to study the role of axon transport in neurological disorders, such as Parkinson’s disease.
Lu X, Kim-Han JS, O’Malley KL, Sakiyama-Elbert SE. A microdevice platform for visualizing mitochondrial transport in aligned dopaminergic axons. Journal of Neuroscience Methods. 209(1):35-9, (2012).
Lu X, Kim-Han JS, Harmon S, Sakiyama-Elbert SE, O’Malley KL. The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons. Mol Neurodegener. 3;9:17, (2014).
Updated January 2019
Development of a Clinically Relevant Model of Infant Traumatic Brain Injury
Principal Investigator: David Brody (formerly WashU Neurology)
Co-investigators: Alexander Parsadanian (WashU Neurology), Philip Bayly (WashU Mechanical Engineering), Krikor Dikranian (WashU Neuroscience)
The human brain undergoes substantial growth and development during the first two years of life. Traumatic brain injury (TBI) during this window is a leading cause of death and disability, and can cause profound alterations of the brain including cognitive dysfunction, attention deficit, hyperactivity and impairment in emotional regulation and judgment. There currently are no effective treatments for TBI other than supportive care, and relatively little research focuses on pediatric TBI compared to other problems of comparable importance. To better understand how infant TBI leads to these behavioral changes, this research project will develop and characterize a clinically relevant mouse model.
Grants and Awards
“Stereotaxic Accessory for Reproducible Neurotrauma”
NIH/NINDS (SBIR Phase II R44 NS46825 – Scouten (PI, Bayly on subcontract to myNeuroLab.com) 9/30/06 – 8/31/08
“Amyloid-β and traumatic brain injury in children”
Thrasher Research Fund (PI, Brody) 1/1/06 – 12/31/08
“Combined Magnetic Resonance Elastography and Diffusion Tensor Imaging of the Brain”
Naval Research Laboratory N00173-14-P-3472, N00173-15-P-6401, N0001417P7002(PIs, Phil Bayly and Anthony Romano, Co-I: Brody) 10/1/14 – 9/30/17
“In Vivo Measurement of Brain Biomechanics”
NIH/NINDS R01 NS055951 (PI, Bayly) 7/1/07 – 11/30/17
“Mechanisms Underlying Amyloid-beta and Tau Pathologies Following Traumatic Brain Injury”
NIH/NINDS R01 NS065069-07 (PI, Brody) 7/1/09-6/30/18
Mac Donald CL, Dikranian K, Bayly P, Holtzman D, Brody D. Diffusion tensor imaging reliably detects experimental traumatic axonal injury and indicates approximate time of injury. J Neurosci.;27(44):11869-76, (2007)
Brody DL, Mac Donald C, Kessens CC, Yuede C, Parsadanian M, Spinner M, Kim E, Schwetye KE, Holtzman DM, Bayly PV. Electromagnetic controlled cortical impact device for precise, graded experimental traumatic brain injury. J Neurotrauma;24(4):657-73, (2007).
Mac Donald CL, Dikranian K, Song SK, Bayly PV, Holtzman DM, Brody DL. Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury. Exp Neurol. ;205(1):116-31, (2007).
Dikranian K, Cohen R, Mac Donald C, Pan Y, Brakefield D, Bayly P, Parsadanian A. Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons. Exp Neurol.;211(2):551-60, (2008).
Shitaka Y, Tran HT, Bennett RE, Sanchez L, Levy MA, Dikranian K, Brody DL. Repetitive closed-skull traumatic brain injury in mice causes persistent multifocal axonal injury and microglial reactivity. J Neuropathol Exp Neurol.;70(7):551-67, (2011).
Updated January 2019