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

糖尿病视网膜病变是导致美国成年人失明的主要原因。尤其是视网膜神经元 容易感染这种疾病，并在发病后不久死亡。视网膜神经元的死亡至少部分是由于 视网膜能量状态的变化：美国，作为视网膜的主要代谢底物，葡萄糖的代谢利用是 在糖尿病方面严重受损。有趣的是，糖尿病期间视网膜细胞被激活的机制还不是很清楚。乳酸是一种单羧酸盐，在视网膜神经元的新陈代谢中起着关键作用；但在糖尿病中，这些神经元必须依赖其他单羧酸盐，即酮体，以满足其高能量需求，因为葡萄糖利用受损。直到最近，视网膜细胞对单羧酸盐的摄取被认为是由质子偶联单羧酸转运体(MCTs)单独介导的。最近，两种新的转运蛋白被发现，它们具有新的能量特征，以钠偶联的电生方式介导细胞对乳酸和酮体的摄取。 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和耐人寻味的不同细胞类型的表达模式表达。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。我们推测，当酮体取代葡萄糖作为能量来源时，这两种转运体是视网膜神经元能量状态的重要决定因素，因此与糖尿病患者的视网膜功能直接相关。本项目的目标是了解SMCT1和SMCT2在视网膜中的生理、病理和临床相关性，特别是在视网膜神经节细胞、Muller细胞和RPE中这些转运体的相关性，我们还将使用一种新的小鼠模型来研究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，该模型显示由于肾脏吸收受损，血液中这些代谢物的水平显著降低。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，从而可能在支持糖尿病视网膜神经元存活方面发挥作用。

Diabetic retinopathy is the leatdhig cause of blindness iamong 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 stat:us, 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 is not well understood. Lactate, a monocarboxylate, plays a key role in the metabolism of retinal neurons; but in 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 solely 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 SMCTl and SMCT2, are expressed in the retina with a very interesting and intriguing expression patterri with the different cell types. SMCTl 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 SMCTl 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 absorption. These studies are critical to understand the molecular events associated with diabetic retinopathy as SMCTl 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 retinal neurons in diabetes.