PROJECT: JTC2022 - Cerebrovascular: MatriSVDs

Cerebral small vessel diseases (cSVDs) are a leading cause of stroke and dementia with no mechanism-based treatments. We aim to provide novel insights into fundamental mechanisms underlying the loss of mural cells and remodeling of the microvascular extracellular matrix (ECM), the two major outcomes common to cSVDs. Our overarching hypothesis is that perturbations of the brain microvascular matrisome— the ensemble of ECM and associated proteins—are a convergent pathway in cSVDs. Our project is articulated around the novel complementary concepts that matrisome changes (i) result from phenotypic switching of vascular/perivascular cells in small brain vessels, (ii) contribute to the loss of mural cells and (iii) are a potential mechanism underlying small brain vessel resilience. Capitalizing on unique resources including multiple clinically relevant cSVD mouse models and large, deeply phenotyped population-based cohorts with extensive molecular characterization, we will: 1) scrutinize phenotypic switching of vascular /perivascular cells in several cSVD mouse models at the single cell level, 2) elucidate the contribution of the HTRA1 matrisome protein in the clinical manifestations and pathogenesis of cSVDs and 3) identify matrisome genes involved in resilience mechanism to cSVD stressors. Each of the 3 aims has the potential to provide entirely new mechanistic insights, a trove of new research questions to explore and therapeutic avenues for these devastating diseases.