Pathobiology of Retinal Vasculopathy with Cerebal Leukodystrophy (RVCL)

血管性认知功能障碍非常普遍，但其生物学基础尚未得到很好的研究。本提案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，这是一种成人发病的常染色体显性卒中综合征，由于全身性微血管病变，在临床、病理学和遗传学上与伴有皮质下梗死和白质脑病的常染色体显性脑动脉病（CADASIL; OMIM 125310）不同。一项合作努力导致最近在TREX 1（一种3 '-5' DNA外切核酸酶）中发现杂合羧基末端移码突变。这些突变蛋白保留了核酸外切酶活性，但失去了TREX 1通常的核周亚细胞定位。TREX 1功能的丧失最近被证明会引发毁灭性的Aicardi-Gutieres综合征和系统性红斑狼疮的自身免疫。TREX 1在维持全身血管完整性和内皮功能中的作用以前尚未被认识到。为什么毛细血管内皮细胞特别容易受到这种普遍表达的蛋白质突变的影响尚不清楚。了解TREX 1突变如何导致系统性血管病变将为治疗干预提供新的策略，并可能为遗传，氧化和辐射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.