Combating cerebral small vessel disease by new diagnostic tools and therapy development

Bakgrund:

A dysfunctional brain vasculature is a well-established aspect of cerebral small vessel disease (SVD) which is responsible for at least 20% of all strokes. CADASIL is the most common genetic SVD and is caused by NOTCH3 mutations, leading to Notch3 aggregates and cell loss in the vessel wall. Målsättning:

In this application, we aim to understand the vascular dysfunction in SVD and to leverage on this for developing new diagnostic tools and advancing therapy development. The work will be conducted under two aims: Arbetsplan:

1) We will use gene expression profiles for all vascular cell types in the mouse brain and identify gene expression changes associated with CADASIL in advanced genetic mouse models. This transcriptomic information will provide candidate genes from which novel biomarkers for CADASIL diagnosis will be established and evaluated in CADASIL patient material to gain new insights into the underlying pathomechanisms for CADASIL.

2) We will use two novel therapeutic approaches to explore ways to restore the brain vascular system; administrating an anti-aggregation chaperone Brichos and a monoclonal antibody towards aggregated Notch3 in CADASIL mouse model and evaluate on both transcriptomic and proteomic level if they have the desired effect in slowing down or halting the disease progress.

Betydelse:

Collectively, we believe that the proposed research will advance the understanding of SVD and provide new diagnostic tools and therapy strategies for CADASIL, a disease that thus far is incurable.