(Provided by the applicant) Abstract: The axon acts as a conduit for organized transport of materials between the cell body and the synapse, a process that is essential for the function and survival of neurons. Defective axonal transport, such as accumulation of axonal cargoes, has been linked with a range of neurodegenerative diseases by extensive genetic and biochemical studies. However, it is still unclear whether and how defective axonal transport might play a role in the progression of neuronal degeneration. Genetic and biochemical approaches lack precise control over when and where the cargo accumulations will happen along the axon, which makes it difficult to pinpoint the role of ""transport defect"" in the process of neuronal degeneration. In this proposal, we propose to engineer magnetic and optical forces that specifically stall a population of axonal cargoes that contain magnetic or optical nanoparticle probes at the trapping area. Physically stalling the cargoes would be one of the most direct means to perturb a cargo transport process, which, however, are technically challenging in live cells. We will overcome those challenges using advanced nanofabrication, imaging techniques and novel nanoparticle probes. Inside the narrow axon, stalled cargoes will act as roadblocks to slow down the trafficking of other probe-free cargoes that are not affected by external forces. Such force-induced traffic jams afford new approaches to investigate whether blocking the axonal transport is sufficient to induce neuronal degeneration and how cellular processes response to axonal traffic blockage. Public Health Relevance: Age-related neurodegenerative diseases, such as Alzheimer's disease, impact the lives of millions and pose a growing public health challenge. This study aims to investigate how defective axonal transport might cause or contribute to the progression of those neurodegenerative diseases. The findings of this research will advance our understanding of age-related neuronal death and assist therapeutic interventions for the treatment of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2NS082125-01
Application #
8358351
Study Section
Special Emphasis Panel (ZGM1-NDIA-C (01))
Program Officer
Ludwig, Kip A
Project Start
2012-09-30
Project End
2017-08-31
Budget Start
2012-09-30
Budget End
2017-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$2,355,000
Indirect Cost
$855,000
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Zhang, Kai; Cui, Bianxiao (2014) Lighting up FGFR signaling. Chem Biol 21:806-8
Lin, Ziliang Carter; Xie, Chong; Osakada, Yasuko et al. (2014) Iridium oxide nanotube electrodes for sensitive and prolonged intracellular measurement of action potentials. Nat Commun 5:3206
Zhang, Kai; Fishel Ben Kenan, Rotem; Osakada, Yasuko et al. (2013) Defective axonal transport of Rab7 GTPase results in dysregulated trophic signaling. J Neurosci 33:7451-62