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

SMCT1

基本信息

批准号：
8114032
负责人：
Pamela M Martin
金额：
$ 23.5万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8114032
关键词：
Adult Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Blindness Blood C57BL/6 Mouse Cell Line Cells Cessation of life Coupled Cryoultramicrotomy Data Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Diclofenac Disease Energy-Generating Resources Event Eye Fenoprofen Glucose Goals Human Hydroxybutyrates Hyperglycemia Ibuprofen Immunofluorescence Immunologic Impairment In Vitro Ketone Bodies Ketoprofen Kidney Knock-out Knockout Mice Laboratories Maintenance Manuscripts Mediating Messenger RNA Metabolic Metabolism Methods Molecular Monitor Morphology Muller&apos s cell Mus Naproxen Neural Retina Neurons Nutrient Pathologic Peer Review Pharmaceutical Preparations Physiological Play Proteins Protons Publishing Radiolabeled Research Retina Retinal Retinal Degeneration Retinal Ganglion Cells Reverse Transcriptase Polymerase Chain Reaction Role Sampling Sodium Streptozocin Streptozocin Diabetes Structure Structure of retinal pigment epithelium System Testing Therapeutic Time Update Urine Work absorption beta-Hydroxybutyrate cell type clinically relevant diabetic ganglion cell insight interest knockout animal meetings mouse model neuron loss neuronal survival nicotinate novel radiotracer retinal neuron uptake

项目摘要

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.

糖尿病视网膜病变是美国成年人失明的主要原因。在疾病中很脆弱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：由于葡萄糖（视网膜中的主要代谢底物）的代谢利用，严重损害了糖尿病。有趣的是，糖尿病期间视网膜细胞通电的机制还不清楚。乳酸盐是一种单羧酸盐，在视网膜神经元的代谢中起着关键作用;但在糖尿病中，由于葡萄糖利用受损，这些神经元必须依赖于其他单羧酸盐，即酮体，以满足其高能量需求。直到最近，视网膜细胞对单羧酸的摄取被认为仅由质子偶联单羧酸转运蛋白（MCT）介导。最近，已经鉴定了两种具有新的能量特征的新转运蛋白，它们以钠偶联的产电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，称为SMCT 1和SMCT 2，在视网膜中以非常有趣和有趣的表达模式表达，具有不同的细胞类型。SMCT 1仅在视网膜神经元和RPE中表达，而SMCT 2主要在Muller细胞中表达。我们假设这两种转运蛋白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，与糖尿病视网膜功能直接相关。本项目的目标是了解SMCT 1和SMCT 2在视网膜中的生理、病理和临床相关性，特别是这些转运蛋白在视网膜神经节细胞、Muller细胞和RPE中的相关性，我们还将使用一种新的小鼠模型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，该模型显示这些物质的水平显著降低。由于肾吸收受损，血液中的代谢物。这些研究对于理解与糖尿病视网膜病变相关的分子事件是至关重要的，因为SMCT 1和SMCT 2可能对维持视网膜神经元的能量状态非常重要，因此可以在支持糖尿病中视网膜神经元的存活中发挥作用。