Graduate Studies Faculty
Jodi McBride, Ph.D.
Neuroscience Graduate Program
Research Interests:Gene therapy, Neuroscience, Neurodegeneration, Huntington's disease, RNA interference, Viral vectors
Preceptor RotationsAcademic Term Available Fall 2016 No Winter 2016 No Spring 2016 No Fall 2017 No Winter 2017 No Spring 2017 No
Faculty MentorshipDr. McBride is not available as a mentor for 2016-2017.
The McBride laboratory focuses the majority of its efforts in finding therapies for neurodegeneratives brain diseases, including Huntington's disease (HD).
HD is a fatal, dominant, neurodegenerative disorder caused by a mutation is an expanded trinucleotide (CAG) repeat in DNA at the IT15 locus on chromosome 4. The mutation HD gene (HTT), in turn, encodes mutant huntingtin protein (HTT) with an expanded polyglutamine (PolyQ) stretch at the N-terminus of the protein.
The characteristic hallmarks of HD neuropathology include mutant HTT-containing aggregates and pronounced cell loss in numerous regions throughout the brain, such as the striatum (comprised of the caudate nucleus and putamen) cortex, thalamus, hypothalamus and the substantia nigra. Although aggregates and cell loss are observed in multiple brain regions, neuropathology is most pronounced in the GABA-ergic, medium-sized spiny neurons of the caudate nucleus and putamen, as well as in the glutamatergic, pyramidal cells of the overlaying cortex.
Clinically, the most obvious symptoms of HD involve involunation hyperkinetic (choreaform) movements of the arms, legs, and face. Additionally, HD patients suffer from cognitive deficits, particularly those involving working (short-term) memory, and personality changes including emotional disturbances such as depression, anxiety, impulsivity and apathy.
Currently, there is no treatment that has a significant impact on the devastating course of the disease. Unlike other neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis, HD is strictly genetic and identification of the genetic marker provides the unique opportunity to intercede therapeutically prior to the onset of symptoms that result from neuronal degeneration. In this vein, therapies that can halt or suppress expression of the diseased gene will likely have the greatest success. RNA interference (RNAi) had recently emerged as a leading candidate approach to reduce expression of disease genes by degrading the encoding mRNA.
The McBride Laboratory is currently investigating RNAi as a potential therapy for HD using a variety of mouse and non-human primate models of the disease. We are currently delivering micro RNAs (miRNAs) that target HTT using different serotypes of recombinant adeno-associated viral vectors (rAAVs) as delivery vehicles. We are interested in assessing the success of these approaches following direct brain injection specifically targeting the striatum, as well as following systemic, vascular delivery of rAAVs that can cross the blood-brain-barrier and transduce cells in multiple brain regions.
Ongoing projects in the laboratory:
1. Assessing the safety and therapeutic efficacy of RNAi in transgenic and knock-in mouse models of HD using a stereotaxic surgical approach
2. Assessing the safety and therapeutic efficacy of RNAi in transgenic and knock-in mouse models of HD using a systemic surgical approach to target multiple brain affected regions (systemic injections into the jugular vein or carotid artery).
3. Developing a nonhuman primate model of HD via rAAV delivery of mutant HTT to the caudate and putamen, with a specific emphasis on trying to recapitulate both the motor and cognitive aspects of the disease.
4. Assessing the therapeutic efficacy of RNAi in a nonhuman primate model of HD.