Drug Discovery for Diabetic Retinopathy

糖尿病视网膜病变的药物发现

• 批准号: 7341818
• 负责人: CHARLES D. SMITH
• 金额: $ 11.52万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341818
• 关键词: biotechnology; combinatorial chemistry; corticosteroid receptors; diabetic retinopathy; drug discovery /isolation; eye agent; membrane proteins; molecular assembly /self assembly; pharmacokinetics; protein biosynthesis; tight junctions; vascular endothelium permeability

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.

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密切相关。据信，正常血视网膜屏障的破坏会破坏正常的视网膜神经元功能。联合首席研究员实验室的研究表明，糖尿病患者眼中的血管内皮生长因子等生长因子含量升高，可通过改变紧密连接蛋白来破坏血-视网膜屏障。相反，糖皮质激素具有相反的作用，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，因为它们会升高血糖，而且局部治疗是侵入性的，可能包括青光眼和白内障形成等副作用。因此，需要鉴定能够特异性诱导血管屏障特性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，在化学库中筛选诱导内皮屏障特性的化合物。筛选方法已经建立，初步数据已经确定了可有效减少跨内皮单层葡聚糖通量的候选化合物。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糖异生的化合物。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，并将检查该化合物对紧密连接蛋白合成和组装的影响。这些实验将提供新颖的先导化合物，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。