Grant: Foundation Grant

Acute Brain Slice; Electrophysiology; Huntington Disease; Neurodegeneration; Nmda Receptor; Optogenetics; Primary Neuronal Culture; Striatum; Synaptic Plasticity; Western Blot

<html> <body> <p>The <strong>overarching focus of my research program</strong> is to determine mechanisms that initiate selective neurodegeneration in brain disease in order to develop disease-modifying therapies. I hypothesize that neuronal vulnerability, leading to cell death, begins with synaptic dysfunction. A particular focus is the N-Methyl-D-aspartate-type glutamate receptor (NMDAR), crucial for synaptic plasticity underlying learning and memory but also a trigger of cell death. As a model for neurodegeneration, I study Huntington disease (HD), a hereditary disorder of mood, movement and cognition in which initially striatum, and then cortex show severe neuronal loss, with devastating impact on patients and families.</p> <p> <strong>Major questions:</strong> <strong>1)</strong> What mechanisms regulate striatal NMDAR function and trafficking? <strong>2)</strong> Why are striatal neurons especially vulnerable to degeneration in HD? Are there differences in NMDAR signaling for corticostriatal and thalamostriatal synapses v. excitatory synapses in cortex? <strong>3)</strong> What role do NMDAR, v. presynaptic or glutamate uptake mechanisms, play in aberrant excitatory synaptic signaling that leads to striatal degeneration? <strong>4)</strong> Can we identify targets for clinical trials to slow HD progression?</p> <p> <strong>Expertise, Impact:</strong> My lab combines electrophysiological, biochemical and optogenetic approaches in neuronal culture, brain slice and animal studies. I am a world leader in corticostriatal synaptic changes that contribute to neuronal vulnerability in HD, and an expert on mechanisms regulating NMDAR. As UBC HD Clinic Director and Site Investigator for international clinical studies, my team is well-positioned to translate lab results to clinical trials and patients. One major finding that received international attention &ndash; inhibition of extrasynaptic NMDAR by memantine restores striatal survival/death signaling balance and improves motor learning in mice &ndash; led to a pilot study of memantine in HD patients, by our UBC clinic team.</p> <p> <strong>Core Team and mentoring:</strong> Technicians with expertise in molecular, biochemical, and neuronal culture methods support trainees, who are skilled in additional techniques required for the research program &ndash; electrophysiology, optogenetics and real-time brain slice imaging. Through weekly meetings and pairing expert lab personnel with new trainees, I ensure effective progress in mastering technical challenges, experimental design, and data analysis. By presenting their work at national/international meetings, and attending local seminars/journal clubs, trainees improve their presentation skills.</p> <p> <strong>Collaborations, vision to advance knowledge and health care applications:</strong> I collaborate with local and international labs for research in HD mouse models, and the Murphy lab (UBC)&nbsp;for real-time imaging of glutamate release/uptake. I collaborated on PREDICT-HD, a multi-centre study to identify markers of progression to diagnosis in premanifest gene mutation carriers, <em>paving the way for clinical trials to delay HD onset</em>. Building on my expertise, experience and collaborations, in the <strong>next seven years my research in HD will accomplish two major goals</strong>: <strong>1)</strong> Determine mechanisms underlying early deficits in excitatory synaptic transmission onto striatal neurons, and altered balance of synaptic/extrasynaptic NMDAR signaling; and <strong>2)</strong> Understand mechanisms of selective neuronal vulnerability by comparing synaptic signaling in cortical v. striatal neurons and at different synapses. Results of these ground-breaking studies will aid development of HD therapies.</p> </body> </html>