Genetic Mosaicism and Molecular Mechanisms inHuman Cerebral Cavernous Malformations

The objective of this application is to investigate the somatic mechanism and the role of the brain microenvironment in familial Cerebral Cavernous Malformation, a common cerebrovascular disease of seizures and hemorrhagic stroke characterized by the presence of vascular lesions (known as CCMs, cavernous angiomas, or cavernomas) in the central nervous system. We will focus on one of the three subtypes of dominantly inherited CCM, underlain by loss-of-function mutations in CCM3, which cause the most aggressive form of this disease. We propose to perform genomic as well as integrated transcriptomic and chromatin accessibility analyses at single-cell resolution to CCMs from a donated brain specimen that harbors multiple lesions at different anatomical locations. We aim to gain unique insight into the genomic, transcriptomic, and epigenetic landscape of CCMs and understand how the local brain microenvironment contributes to lesion formation. We will extend analyses to additional surgical specimens of lesions, aiming to discover and define underlying unifying molecular principles of CCM pathogenesis. Project Number: 1R21NS142542-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Angeliki Louvi | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $462,151 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 MGG-R (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11369381