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Michael Wang

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Primary Appointment: Neurology Department
Primary PIBS Dept.: Neuroscience
Other PIBS Depts.: Molecular and Integrative Physiology
PubMed Name: wang mm
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Stroke is a devasating disorder that causes permanent disability and death. Consequently, there is an urgent need to develop effective preventative strategies and treatments. New therapies will be made possible through a basic understanding of the molecular and cellular mechanisms of stroke. Our lab focuses on the mechanisms of proteins in the brain vasculature and cell biology of vascular cells in stroke.

A major effort in the lab is to understand the mechanism of CADASIL, one of the best known inherited stroke syndromes. CADASIL causes early onset stroke, dementia, and migraine with aura. CADASIL patient have mutations in Notch3, which likely result in structural changes in the protein that cause protein accumulation, cell adhesive defects, and Notch3 buildup. We are using biochemical, molecular, cell culture, and mouse genetic approaches to decipher the mechanisms by which a single notch3 mutation ultimately leads to a complex, debilitating disease.

Recent work has shown that thrombospondin-2 binds to Notch3. We are characterizing this interaction in detail and delineating the physiological and pathological significance of this molecular interaction. It appears that thrombospondin-2 may modulate Notch3 signaling; we are now trying to uncover whether molecular partnering between the two proteins results in some of the cellular features of CADASIL.

Another line of research is to further characterize genetically modified mice which express a CADASIL mutant form of Notch3. We have also constructed mice that express a constitutively active Notch3 isoform. We will use these mice to study the biochemistry and cell biology of the Notch3 mutation. Ultimately, these mice may be useful to investigate CADASIL therapies and basic biology of Notch signaling. In pursuit of these investigations, we have a number of active collaborations with extramural investigators.

Other projects in the lab include active collaborations with Dr. Jimo Borjigin (UM) to study reciprocal interactions between the circadian system and stroke, serotonin/melatonin biochemistry, and adaptation to neuronal injury. We have a long standing collaboration with Dr. Pam Lein (OHSU) to study the molecular biology of BMP signaling in neurons.