Sphingosine 1-Phosphate: A New Target for Early Diabetic Retinopathy

1-磷酸鞘氨醇：早期糖尿病视网膜病变的新靶点

• 批准号: 8440051
• 负责人: ARUP DAS
• 金额: --
• 依托单位: ALBUQUERQUE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440051
• 关键词: Accounting; Adhesions; Adult; Affect; Animal Model; Animals; Bed Occupancy; Blindness; Blood; Blood Vessels; Blood-Retinal Barrier; Cell Communication; Cells; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diagnosis; Disease; Effectiveness; Endothelial Cells; Enrollment; Epidemic; Event; Functional disorder; General Population; Goals; Histologic; Human; Intercellular Junctions; Lasers; Leukocytes; Literature; Maintenance; Microcirculation; Modeling; Molecular; N-Cadherin; Neuroglia; Normal Cell; Pathway interactions; Patients; Pericytes; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Pharmacy facility; Phosphotransferases; Play; Prevalence; Process; Public Health; Regulation; Research; Retina; Retinal; Retinal Edemas; Role; Sphingosine-1-Phosphate Receptor; Testing; Vascular Endothelial Growth Factors; Vascular Permeabilities; Veterans; Vision; Work; base; cost; diabetic; health administration; hospital bed; innovation; intravitreal injection; macular edema; middle age; new therapeutic target; novel; novel therapeutic intervention; prevent; protein expression; public health relevance; response; retina blood vessel structure; sphingosine 1-phosphate; therapeutic target

DESCRIPTION (provided by applicant): Diabetes is a global epidemic with 246 million people affected, and the prevalence is expected to double by 2030. The disease represents a significant public health problem. Diabetes within the Veterans Health Administration (VHA) poses a significant challenge because the estimated prevalence of diabetes among its enrolled patients is as high as 20%, substantially higher than the general population. Diabetes is the third most common VHA diagnosis and accounted for 25% of pharmacy costs and over 1.7 million hospital bed days. Diabetic retinopathy is the leading cause of vision loss in middle-aged adults. Despite the use of therapeutics targeting the vascular endothelial growth factor (VEGF), the majority of patients do not recover vision, and the effect is transient, needing repeated intravitreal injections of drugs. Our long-term goal is o fully characterize a novel pathway, sphingosine 1 phosphate (S1P) in diabetic retinopathy, and identify novel targets for the treatment of this blinding condition, macular edema. Pericyte loss is the classic histologic finding of early diabetic retinopathy in the human retina. It is possibl that earlier "pericyte dysfunction" occurs even before pericyte loss. It is not known how this pericyte change in diabetes further leads to increased vaso-permeability in retinal vessels. In new and exciting findings, we have shown that pericytes can regulate the expression of N- cadherin in endothelial cells that is necessary for proper endothelial-pericyte interactions, and that perictyes produce sphingosine 1 phosphate (S1P), among other molecules, that appears to play a role in the regulation of endothelial barrier function. The central hypothesis of this proposal is that pericyte- derived sphingosine 1-phosphate (S1P) maintains the normal Blood-Retinal Barrier and disruption of the S1P pathway in early diabetic retinopathy leads to the alteration of cell-cell interactions and changes in vascular permeability. The rationale for the proposed research is that understanding the mechanism of the S1P pathway in diabetes will help us in identifying novel targets that can prevent or reverse the damage to the blood-retinal barrier in macular edema, that afflict 14- 25% of all patients with diabetes. Based on our preliminary data, we will test the hypothesis with the following specific aims: i) to identify the mechanisms by which pericytes contribute to the maintenance of the blood-retinal barrier ii) to determine the extent to which diabetes modifies endothelial-pericyte interactions and components of the S1P pathway leading to breakdown of the blood-retinal-barrier and iii) to evaluate the effectiveness of compounds that target the components of the S1P pathway to prevent or reverse increased retinal vascular permeability in the diabetic animal. The proposed research is significant because the study will help us to better understanding how pericytes normally contribute to the stabilization of cell-cell junctions and the blood-retinal barrier, and how this process may be disrupted during the development of diabetic retinopathy. Our approach is innovative because this proposal introduces an innovative strategy that targets the mechanisms of stabilizing the initial step of pericyte dysfunction in diabetes, a critical upstrea event for the development of diabetic macular edema. ))

描述(由申请人提供)： 糖尿病是一种全球流行病，有2.46亿人受到影响，预计到2030年，患病率将翻一番。这种疾病是一个重大的公共卫生问题。退伍军人健康管理局(VHA)内的糖尿病构成了一个重大挑战，因为据估计，其登记患者中的糖尿病患病率高达20%，大大高于普通人群。糖尿病是第三种最常见的VHA诊断，占药房费用的25%，住院天数超过170万天。糖尿病视网膜病变是导致中年人失明的主要原因。尽管使用了针对血管内皮生长因子(VEGF)的治疗药物，但大多数患者无法恢复视力，而且效果是短暂的，需要反复玻璃体内注射药物。我们的长期目标是充分描述糖尿病视网膜病变中的一种新途径，即1-磷酸鞘氨醇(S1P)，并确定治疗这种致盲疾病--黄斑水肿的新靶点。周细胞丢失是人类视网膜早期糖尿病视网膜病变的经典组织学表现。有可能早期的“周细胞功能障碍”甚至发生在周细胞丢失之前。目前尚不清楚糖尿病患者的这种周细胞改变如何进一步导致视网膜血管通透性增加。在新的和令人兴奋的发现中，我们已经表明周细胞可以调节内皮细胞中N-钙粘素的表达，这是内皮细胞与周细胞正确相互作用所必需的，并且周细胞产生鞘氨醇1磷酸(S1P)等分子，似乎在调节内皮屏障功能中发挥作用。这一假设的核心假设是，周细胞来源的鞘氨醇1-磷酸(S1P)维持正常的血-视网膜屏障，在早期糖尿病视网膜病变中，S1P通路的破坏导致细胞-细胞相互作用的改变和血管通透性的变化。提出这项研究的理由是，了解糖尿病中S1P通路的机制将有助于我们确定新的靶点，可以预防或逆转黄斑水肿对血-视网膜屏障的破坏，所有糖尿病患者中有14%-25%受到黄斑水肿的困扰。根据我们的初步数据，我们将以以下具体目标检验假设：i)确定 2)确定糖尿病对内皮细胞-周细胞的相互作用及S1P通路的组成部分可在多大程度上改变导致血-视网膜屏障破裂的S1P通路成分；及iii)评价针对S1P通路成份的化合物在预防或逆转糖尿病动物视网膜血管通透性增加方面的有效性。这项拟议的研究意义重大，因为这项研究将帮助我们更好地了解周细胞通常如何有助于细胞-细胞连接和血-视网膜屏障的稳定，以及 在糖尿病视网膜病变的发展过程中，这一过程是如何被破坏的。我们的方法是创新的，因为这项建议引入了一种创新的策略，旨在稳定糖尿病周细胞功能障碍的初始步骤的机制，这是糖尿病黄斑水肿发展的关键上游事件。))