■最近的研究表明,视网膜色素上皮(RPE)依靠脂肪酸氧化(FAO)获得能量,然而,它在整体视网膜健康中的作用是未知的。唯一表现为脉络膜视网膜病变的FAO疾病是长链3-羟基酰基-CoA脱氢酶缺乏症(LCHADD)。研究分子机制可以为患者带来新的治疗方法,并阐明FAO在RPE中的作用。本文描述了最近报道的LCHADD小鼠模型中脉络膜视网膜病变的进展。
■视觉评估,如光动力学跟踪和眼底成像,在3、6、10和12月龄的野生型(WT)和LCHADD小鼠中进行。使用苏木精和曙红(H&E)在12个月的视网膜横截面中分析视网膜形态,RPE65、CD68和TUNEL染色,而RPE结构是使用透射电子显微镜(TEM)评估的。在分离的RPE/巩膜样品中测量酰基肉碱谱以确定FAO是否被阻断。12月龄雄性WT小鼠和LCHADDRPE/巩膜样品的大量RNA测序评估了基因表达变化。
■与WT相比,LCHADDRPE/巩膜样品的长链羟基酰基肉碱增加了5至7倍,表明LCHAD在长链粮农组织中的一个受损步骤。从6个月开始,LCHADD小鼠的视力逐渐下降,RPE变性增加。LCHADDRPE具有改变的结构,并且在视网膜下隙中巨噬细胞增加了两倍。最后,与WT相比,LCHADDRPE/巩膜具有差异表达的基因,包括对RPE功能和血管生成重要的基因的下调。
■总的来说,该LCHADD小鼠模型概括了在LCHADD患者中观察到的早期脉络膜视网膜病变,是研究LCHADD脉络膜视网膜病变的有用模型.
UNASSIGNED: Recent studies have shown that the retinal pigment epithelium (RPE) relies on fatty acid oxidation (FAO) for energy, however, its role in overall retinal health is unknown. The only FAO disorder that presents with chorioretinopathy is long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). Studying the molecular mechanisms can lead to new treatments for patients and elucidate the role of FAO in the RPE. This paper characterizes the chorioretinopathy progression in a recently reported LCHADD mouse model.
UNASSIGNED: Visual assessments, such as optokinetic tracking and fundus imaging, were performed in wildtype (WT) and LCHADD mice at 3, 6, 10, and 12 months of age. Retinal morphology was analyzed in 12-month retinal cross-sections using hematoxylin and eosin (H&E), RPE65, CD68, and TUNEL staining, whereas RPE structure was assessed using transmission electron microscopy (TEM). Acylcarnitine profiles were measured in isolated RPE/sclera samples to determine if FAO was blocked. Bulk RNA-sequencing of 12 month old male WT mice and LCHADD RPE/sclera samples assessed gene expression changes.
UNASSIGNED: LCHADD RPE/sclera samples had a 5- to 7-fold increase in long-chain hydroxyacylcarnitines compared to WT, suggesting an impaired LCHAD step in long-chain FAO. LCHADD mice have progressively decreased visual performance and increased RPE degeneration starting at 6 months. LCHADD RPE have an altered structure and a two-fold increase in macrophages in the subretinal space. Finally, LCHADD RPE/sclera have differentially expressed genes compared to WT, including downregulation of genes important for RPE function and angiogenesis.
UNASSIGNED: Overall, this LCHADD mouse model recapitulates early-stage chorioretinopathy seen in patients with LCHADD and is a useful model for studying LCHADD chorioretinopathy.