Interdisciplinary Initiatives Program Round 8 - 2016

Ellen Kuhl, Mechanical Engineering and Bioengineering
Soichi Wakatsuki, Structural Biology and Photon Science

Traumatic brain injury is a mechanical insult to the brain that affects more than one million people in the United States every year. We now know that even mild concussions can trigger progressive neurological degeneration, a condition that is increasingly recognized as chronic traumatic encephalopathy. Currently, there is no way to diagnose chronic traumatic encephalopathy during life; it can only be diagnosed after death by histopathological analysis. In the brain of a healthy person, nerve cells transmit electrical signals through thin, long cables called axons. These axons are made up of microtubules, which are assembled into well-organized, evenly spaced bundles by tau proteins. Progressive failure of the tau-microtubule complex and gradual axonal degradation are classic hallmarks of chronic traumatic encephalopathy. Strikingly, these symptoms appear to be shared by a number of other neurodegenerative diseases including Alzheimer’s disease and Parkinsonism. However, to date, the molecular mechanisms of neurodegeneration remain poorly understood. The objective of this research is to probe, model, and simulate tau-microtubule interaction to provide fundamental insight into the molecular and cellular mechanisms of axonal failure during chronic traumatic encephalopathy. In a new collaboration between SLAC National Accelerator Laboratory and Stanford University, this research will catalyze discovery by crossing the boundaries between Photon Science, Structural Biology, Mechanical Engineering, and Bioengineering and combine innovative solutions including cryo-electron microscopy, molecular dynamics, small angle X-ray scattering, kinogeometric sampling, axonal stretching, and multiscale modeling to characterize the effects of physical stimuli on normal and abnormal axonal behavior. Using an unconventional, multidisciplinary approach, we will probe landscapes of interacting intracellular events at their intrinsic spatial and temporal scales and predict the timeline of progressive degeneration. In benefit of human health, our immediate deliverable is a macro-exposure/micro-response relationship to characterize failure thresholds and safety limits of neurodegeneration across the scales. Ultimately, a better mechanistic understanding of the tau-microtubule complex could radically change our understanding of chronic traumatic encephalopathy and help identify potential drug targets and inhibitors to slow down, block, or reverse neurodegeneration.