Drug Discovery for Diabetic Retinopathy

描述（由申请人提供）： 糖尿病视网膜病变是美国失明的主要原因之一，导致黄斑水肿的血管通透性与视力丧失高度相关。正常血-视网膜屏障的破坏被认为会破坏正常的视网膜神经元功能。来自co-PI实验室的研究表明，生长因子如血管内皮生长因子，在糖尿病患者的眼睛中升高，通过改变紧密连接蛋白来破坏血液-视网膜屏障。相反，糖皮质激素具有相反的作用，并通过刺激紧密连接蛋白的合成和组装来诱导屏障特性。糖皮质激素不能全身给予糖尿病患者，因为其葡萄糖升高作用和局部治疗是侵入性的，可能包括副作用，如青光眼和白内障形成。因此，需要鉴定特异性诱导血管屏障性质而没有这些副作用的新型化合物。为了鉴定这些化合物，我们将与宾夕法尼亚州立大学医学院药物发现核心设施主任Charles Smith博士合作，筛选诱导内皮屏障特性的化合物的化学库。筛选方法已经建立，初步数据已经确定了候选化合物，有效地减少葡聚糖通过内皮细胞单层的流量。具体目标1将使用一系列筛选来鉴定诱导血管屏障特性但不诱导肝细胞中的血管生成的化合物。具体目标2将研究先导化合物的作用机制。实验将揭示糖皮质激素受体在候选化合物的作用中是否是必需的，并将检查化合物对紧密连接蛋白合成和组装的影响。这些实验将提供新的先导化合物，这些化合物将被进一步开发用于治疗糖尿病视网膜病变中的黄斑水肿。

DESCRIPTION (provided by applicant): Diabetic retinopathy is one of the leading causes of blindness in the United States and vascular permeability resulting in macular edema is highly associated with vision loss. Breakdown of the normal blood-retinal barrier is believed to disrupt normal retinal neuronal function. Research from the laboratory of the co-PI has demonstrated that growth factors such as vascular endothelial growth factor, which are elevated in the eyes of patients with diabetes, breakdown the blood-retinal barrier by altering tight junction proteins. Conversely, glucocorticoids have the opposite effect and induce barrier properties by stimulating the synthesis and assembly of tight junction proteins. Glucocorticoids cannot be given systemically to patients with diabetes because of their glucose elevating effects and local treatment is invasive and may include side effects such as glaucoma and cataract formation. Therefore, a need exists to identify novel compounds that specifically induce vascular barrier properties without these side effects. In order to identify these compounds we will partner with Dr. Charles Smith, Director of the Drug Discovery Core Facility at the Penn State College of Medicine to screen a chemical library for compounds that induce endothelial barrier properties. Screening methods have been established and preliminary data have already identified candidate compounds that are effective in reducing dextran flux across endothelial monolayers. Specific aim 1 will use a series of screens to identify compounds that induce vascular barrier properties but that do not induce gluconeogenesis in hepatocytes. Specific aim 2 will investigate the mechanism of action of lead compounds. Experiments will reveal whether the glucocorticoid receptor is necessary in the action of the candidate compound and the effect of the compound on tight junction protein synthesis and assembly will be examined. These experiments will provide novel, lead compounds that will be further developed to treat macular edema in diabetic retinopathy.