Pathobiology of Retinal Vasculopathy with Cerebal Leukodystrophy (RVCL)

血管性认知障碍非常普遍，但其生物学基础尚未得到很好的研究。该建议的目的是阐明视网膜血管病变伴脑白质营养不良（RVCL; OMIM 192315）的分子和细胞病理过程，RVCL是一种常染色体显性卒中综合征，成人发病，由于系统性微血管病变，在临床、病理和遗传学上不同于脑常染色体显性动脉病变伴皮层下梗死和脑白质脑病（CADASIL; OMIM125310）。最近在TREX1（一种3 ' -5 ' DNA外切酶）中发现了杂合羧基端移码突变。这些突变蛋白保留了外切酶活性，但失去了TREX1通常的核周亚细胞定位。TREX1功能的丧失最近被证明在破坏性阿卡蒂-古铁雷斯综合征和系统性红斑狼疮中触发自身免疫。TREX1在维持全身血管完整性和内皮功能方面的作用以前没有被认识到。为什么毛细血管内皮细胞特别容易受到这种无处不在的表达蛋白突变的影响尚不清楚。了解TREX1突变如何导致全身性血管病变将为治疗干预提供新的策略，并可能为遗传、氧化和辐照内皮损伤的可能共享机制提供见解。

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.