SMCT1 & SMCT2: expression in retina & relevance to diabetic retinopathy

描述（由申请人提供）：糖尿病视网膜病变是美国成年人失明的主要原因，视网膜神经元在该疾病中特别脆弱，发病后不久就会死亡。视网膜神经元的死亡至少部分是由于视网膜能量状态的改变，因为糖尿病患者对视网膜主要代谢底物葡萄糖的代谢利用严重受损。有趣的是，糖尿病期间视网膜细胞被激活的机制是，这些神经元必须依靠其他单羧酸盐，即酮体，来满足由于葡萄糖利用受损而产生的高能量需求。直到最近，视网膜细胞对单羧酸盐的摄取被认为仅仅是由质子偶联的单羧酸转运体（mct）介导的。最近，发现了两种具有新能量特征的转运体，它们以钠偶联电致方式介导乳酸和酮体的细胞摄取。我们有证据表明，这两种转运蛋白，即SMCT1和SMCT2，在视网膜中以一种非常有趣的表达模式在不同的细胞类型中表达。SMCT1仅在视网膜神经元和RPE中表达，而SMCT2主要在Muller细胞中表达。我们假设这两种转运体是视网膜神经元能量状态的重要决定因素，因此当酮体取代葡萄糖作为能量来源时，它们与糖尿病视网膜功能直接相关。当前项目的目标是了解SMCT1和SMCT2在视网膜中的生理、病理和临床相关性，特别是这些转运体在视网膜神经节细胞、Muller细胞和RPE中的相关性。我们还将研究在正常和糖尿病条件下循环乳酸和酮体对视网膜能量状态的重要性，使用一种新的小鼠模型，该模型显示由于肾脏重吸收受损，血液中这些代谢物的水平显着降低。这些研究对于了解与糖尿病视网膜病变相关的分子事件至关重要，因为SMCT1和SMCT2可能对维持视网膜神经元的能量状态非常重要，因此可能在支持糖尿病视网膜神经元的存活中发挥作用。

DESCRIPTION (provided by applicant): Diabetic retinopathy is the leading cause of blindness among adults in the U. S. Retinal neurons are particularly vulnerable in the disease and die shortly after its onset. This death of retinal neurons is at least partly due to changes in retinal energy status, as metabolic utilization of glucose, the principal metabolic substrate in retina, is severely compromised in diabetes. Interestingly, the mechanism by which cells in the retina are energized during diabetes, these neurons must rely upon other monocarboxylates, namely ketone bodies, to meet their high energy demands because of impairment of glucose utilization. Until recently, uptake of monocarboxylates by retinal cells was thought to be mediated soley by the proton-coupled monocarboxylate transporters (MCTs). Recently, two new transporters with novel energetic features have been identified which mediate the cellular uptake of lactate and ketone bodies in a sodium-coupled electrogenic manner. We have evidence to show that these two transporters, known as SMCT1 and SMCT2, are expressed in the retina with a very interesting and intriguing expression pattern with the different cell types. SMCT1 is expressed exclusively in retinal neurons and RPE whereas SMCT2 principally in Muller cells. We hypothesize that these two transporters are important determinants of energy status in retinal neurons and thus are directly relevant to retinal function in diabetes when ketone bodies replace glucose as the energy source. The goal of the current project is to understand the physiologic, pathologic, and clinical relevance of SMCT1 and SMCT2 in the retina, particularly the relevance of these transporters in retinal ganglion cells, Muller cells, and RPE. We will also investigate the importance of circulating lactate and ketone bodies to retinal energy status under normal and diabetic conditions using a novel mouse model which shows markedly reduced levels of these metabolites in blood due to impaired renal reabsorption. These studies are critical to understand the molecular events associated with diabetic retinopathy as SMCT1 and SMCT2 are likely to be very important to the maintenance of energy status of retinal neurons and thus may play a role in supporting survival of the retinal neurons in diabetes.