Vascular cognitive impairment is highly prevalent, yet its biological basis has not been well studied. The goal of this proposal is to elucidate the molecular and cellular pathological processes underlying retinal vasculopathy with cerebral leukodystrophy (RVCL;OMIM 192315), an autosomal dominant stroke syndrome of adult onset due to a systemic microvasculopathy that is clinically, pathologically, and genetically distinct from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL;OMIM125310). A collaborative effort led to the recent discovery of heterozygous carboxyl-terminal frameshift mutations in TREX1, a 3'-5'DNA exonuclease. These mutant proteins retain exonuclease activity but lose the usual perinuclear subcellular localization of TREX1. The loss of TREX1 function was recently shown to trigger autoimmunity in devastating Aicardi-Gutieres syndrome and systemic lupus erythematosus. A role for TREX1 in the maintenance of systemic vascular integrity and endothelial function has not been previously recognized. Why capillary endothelial cells are especially vulnerable to mutations in this ubiquitously expressed protein is not known. Understanding how TREX1 mutations lead to systemic vasculopathy will provide new strategies for therapeutic intervention and may provide insight to possibly shared mechanisms in inherited, oxidative, and irradiation endothelial damage.