Stroke is a leading cause of death and disability in the US. Of the 795,000 new strokes per year, approximately 25% of these strokes are termed small vessel strokes affecting brain white matter, producing significant disability and cognitive decline. The use of magnetic resonance imaging demonstrates that white matter strokes expand and patient's disability progresses, often while patients remain under care in the hospital. This lost therapeutic opportunity is due, in part, to a poor understanding of the molecular events that follow white matter stroke, particularly those that involve the unique cellular elements of brain white matter: the axoglial unit. Injury to white matter disrupts the molecular connection between the myelinating oligodendrocyte, the axon, and its associated neuronal cell body (the axoglial unit) resulting in progressive axonal degeneration and stroke expansion. Studies in this grant will employ a novel mouse model of white matter stroke to identify the cellular and molecular mechanisms of cell-cell adhesion and energy transfer within the axoglial unit that lead to progressive axonal degeneration and stroke expansion. In addition, the retrograde effects of white matter stroke on the proximal axonal segment of the neuronal cell body far from the site of injury will be determined. These goals reflect my immediate career objectives of achieving an improved understanding of the molecular events associated with white matter stroke and micro vascular disease of the brain. Over the long-term, I plan to use this knowledge to design new molecular therapeutics for the treatment of stroke, acting to reduce the burden of stroke and stroke-related disability through my research, therapeutic development, and academic leadership. This mentored award will provide specific advanced training in rodent stroke modeling, laser capture micro dissection, RNAseq exome sequencing, and in vivo gene manipulation strategies. This training will be conducted under the direction of Dr. S. Thomas Carmichael, a leader in translational stroke research and co-mentored by Dr. Jeffrey Saver, a world leader in clinical stroke science. A career development plan providing training in these molecular techniques and the strategies needed to translate bench findings into therapeutics will be acquired through regular meetings with these mentors, carefully selected coursework, and hands-on experience. The University of California Los Angeles has a large and active academic neurology department that is well-recognized for training clinician-scientists. The proposed work will also take advantage of the resources available at UCLA in scientific cores and through established collaborations within the Department of Neurology. The UCLA Department of Neurology is committed to the advancement of my academic career and will provide a structured and supportive environment for the early stage of my career.
Many neurologic diseases include damage to brain white matter and the axons and myelinating oligodendrocytes that make up this essential tissue. Chief among these diseases is stroke; the fourth leading cause of death and a leading source of disability in the US. This project investigates the role of a unique multicellular system consistin of the neuron, the axon, and the oligodendrocyte in the progression of white matter stroke. A detailed understanding of the biology of this system in stroke progression will lead to new therapeutic strategies for the treatment of stroke.
