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

描述（由申请人提供）： 糖尿病是一种全球流行病，有2.46亿人受影响，预计到2030年患病率将翻一番。这种疾病是一个严重的公共卫生问题。退伍军人健康管理局（VHA）内的糖尿病构成了一个重大挑战，因为其登记的患者中糖尿病的估计患病率高达20%，大大高于一般人群。糖尿病是第三常见的VHA诊断，占药房费用的25%，超过170万个住院日。糖尿病视网膜病变是中年人视力丧失的主要原因。尽管使用靶向血管内皮生长因子（VEGF）的治疗剂，但大多数患者不能恢复视力，并且效果是短暂的，需要反复玻璃体内注射药物。我们的长期目标是充分表征糖尿病视网膜病变中的新途径1磷酸鞘氨醇（S1 P），并确定治疗这种致盲性疾病黄斑水肿的新靶点。周细胞丢失是人类视网膜中早期糖尿病视网膜病变的经典组织学发现。有可能在周细胞丧失之前就发生早期的“周细胞功能障碍”。目前尚不清楚糖尿病中的周细胞变化如何进一步导致视网膜血管中血管通透性增加。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的N-钙粘蛋白的表达，这是必要的适当的内皮-周细胞的相互作用，并且周细胞产生鞘氨醇1磷酸（S1 P），以及其他分子，这似乎在内皮屏障功能的调节中发挥作用。该提议的中心假设是周细胞衍生的鞘氨醇1-磷酸（S1 P）维持正常的血视网膜屏障，并且在早期糖尿病视网膜病变中S1 P途径的破坏导致细胞-细胞相互作用的改变和血管通透性的变化。这项研究的基本原理是，了解糖尿病中S1 P通路的机制将有助于我们确定新的靶点，这些靶点可以预防或逆转黄斑水肿对血视网膜屏障的损害，黄斑水肿困扰着14- 25%的糖尿病患者。根据我们的初步数据，我们将测试假设与以下具体目标：i）确定 周细胞有助于维持血-视网膜屏障的机制，ii）确定糖尿病改变内皮-周细胞相互作用和导致血-视网膜屏障破坏的S1 P途径组分的程度，和iii）评价靶向S1 P途径组分的化合物预防或逆转糖尿病动物中视网膜血管通透性增加的有效性。这项研究意义重大，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连接和血视网膜屏障的稳定， 这一过程在糖尿病视网膜病变的发展过程中是如何被破坏的。我们的方法是创新的，因为该建议引入了一种创新的策略，该策略针对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。 ))

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. ))