Signaling Aberrations and Cerebral Cavernous Malformations Pathogenesis. In the first cycle of this program project our collaborative group has made significant discoveries concerning CCM pathogenesis. In this renewal we will follow up these discoveries towards a scientifically based therapy. Recent data from multiple laboratories in our program converge on a model in which somatically mutated, CCM-deficient endothelial cells poison the peri-lesional environment to recruit non-deficient cells into the growing lesion. We will investigate the molecular and cellular basis for this non-cell autonomous pathological mechanism, including single-cell genomic and transcriptomic analyses in mouse and human lesions and mechanistic studies in mouse models. We have also discovered that endothelial cells within murine and human CCMs express markedly increased levels of thrombomodulin and endothelial protein C receptor which leads to activation of endogenous anti-coagulant protein C. This discovery provides a new target for lesional hemorrhage, the most clinically significant phenotype associated with CCM. Importantly, to enable these and other studies we have generated new, more robust CCM mouse models that exhibit both rapid lesion growth and lesional hemorrhage. We have also identified an unexpected and novel signaling aberration involved in CCM growth ? activation of PI3 kinase ? a target with existing drugs and with others under development. We will investigate the role of PI3 kinase in CCM lesion growth and its inhibition as a potential therapy. In parallel, we will search for somatic mutations in other genes that might enable repurposing of other existing drugs for CCM therapy. By capitalizing on our successes over the past four years, our renewal is designed to move from discovery, to mechanism, and then on to investigation of therapies for CCM disease.
Signaling Aberrations and Cerebral Cavernous Malformations Pathogenesis Cerebral Cavernous Malformations (CCM) are blood vessel abnormalities occurring in the brain. The CCMs can bleed and cause seizures or strokes. In this renewal application of a program project, four leading laboratories working on this disease will continue our investigation into the underlying processes that cause the CCMs to form, and to cause them to bleed. Using mice that we have genetically engineered to have the disease and comparing these animals with tissue and blood from human CCM patients, we will work towards a fuller understanding of the disease with the goal of generating new ideas for therapy.
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