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.
We recently identified the genetic cause of RVCL (retinal vasculopathy with cerebral leukodystrophy), which, like CADASIL, is a familial stroke syndrome that damages white matter in the brain and causes progressive cognitive decline. Studying the molecular mechanisms underlying this newly defined familial stroke syndrome will identify new targets for treatment and help us understand cellular processes that are important in maintaining normal vascular function in health and disease. ARRA Importance: The proposed studies are in-keeping with the spirit of the ARRA to stimulate the economy by creating (1.0 FTE/retaining - 1.9 FTE) jobs and by purchasing equipment (microscope accessories and cryobiological storage system and laboratory supplies to make scientific process in two years in performing innovative research with broad clinical relevance.
| Kothari, Parul H; Kolar, Grant R; Jen, Joanna C et al. (2018) TREX1 is expressed by microglia in normal human brain and increases in regions affected by ischemia. Brain Pathol 28:806-821 |
| Namjou, B; Kothari, P H; Kelly, J A et al. (2011) Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 12:270-9 |
| Mateen, F J; Krecke, K; Younge, B R et al. (2010) Evolution of a tumor-like lesion in cerebroretinal vasculopathy and TREX1 mutation. Neurology 75:1211-3 |
