Understanding the mechanism and downstream consequences of Notch3ECD accumulation and developing Notch3-related biological markers in the rare disease CADASIL. – CadaNotch

CADASIL is an autosomal dominant small vessel disease of the brain leading to severe disability and cognitive decline without specific treatment. The disease is caused by highly stereotyped mutations in the NOTCH3 receptor leading to the abnormal accumulation of the extracellular domain of NOTCH3 (Notch3ECD) around mural cells of small vessels that ultimately degenerate. Yet, our understanding of the molecular mechanisms underlying CADASIL pathogenesis is still incomplete. Here we propose a translational research project which aims at: 1) Elucidating the mechanism of Notch3ECD accumulation, 2) Investigating the downstream mechanisms by which Notch3ECD accumulation causes small vessel pathology and 3) Developing NOTCH3-related biological biomarkers to monitor disease progression. Our proposal rests on a foundation constructed from novel working hypotheses supported by ample preliminary data and takes advantage of novel methodological approaches and unique resources developed by members of this consortium, including but not limited to a wide array of mouse models, a large cohort of CADASIL patients as well as biological fluids and induced pluripotent stem cells from these patients.