Sphingosine Kinase Inhibitors of Diabetic Retinopathy

糖尿病视网膜病变的鞘氨醇激酶抑制剂

• 批准号: 6933599
• 负责人: LYNN W MAINES
• 金额: $ 12.93万
• 依托单位: APOGEE BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933599
• 关键词: alcohol phosphotransferase; angiogenesis inhibitors; athymic mouse; diabetes mellitus therapy; diabetic retinopathy; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; eye disorder chemotherapy; fibroblast growth factor; laboratory rat; nonhuman therapy evaluation; sphingosine; vascular endothelial growth factors

DESCRIPTION (provided by applicant): The long-term goal of this program is to identify and develop novel inhibitors of human sphingosine kinase (SK) that are effective as therapeutic agents. Because of its critical role in sphingolipid metabolism and angiogenesis, we have focused on SK as an innovative molecular target for the development of new drugs for the treatment of diabetic retinopathy. Sphingolipids are being increasingly recognized as key mediators of apoptosis, stress responses, cell differentiation and proliferation, and are known to interact with key players in the angiogenic cascade of central importance in diabetic retinopathy. Specifically, sphingosine-1-phosphate (S1P) produced by SK mediates the effects of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and protein kinase C (PKC), all having critical roles in the manifestations of diabetic retinopathy. Therefore, SK is a key molecular target for the development of new therapeutic agents for this disease. In spite of accumulating evidence for a pivotal role of SK in regulating proliferation and angiogenesis, pharmacological inhibition of SK is an untested means of treating an angiogenic-based disease such as diabetic retinopathy. This is largely due to the heretofore lack of pharmacologically useful SK inhibitors. To overcome this problem, we have recently identified novel inhibitors of human SK. We hypothesize that these SK inhibitors will be useful to block the deleterious angiogenic effects of VEGF and bFGF, and thereby ameliorate diabetic retinopathy. To provide proof-of-principle evaluations of the utility of these compounds, the following Specific Aims will be addressed in Phase I of this project: 1). To synthesize sufficient amounts of three SK inhibitors for in vitro and in vivo studies. 2). To determine the in vitro effects of these SK inhibitors on the VEGF- and bFGF-mediated signaling cascades that contribute to angiogenesis. 3). To evaluate the in vivo toxicities and therapeutic efficacies of SK inhibitors in two rodent models of diabetic retinopathy. Because of our previous work that led to the identification of these compounds and the development of methods for their synthesis, as well as the demonstrated expertise of our Consultant with diabetic retinopathy models, we are currently in a unique position to undertake the proposed studies.

描述（由申请人提供）：本项目的长期目标是鉴定和开发有效作为治疗剂的新型人鞘氨醇激酶（SK）抑制剂。由于其在鞘脂代谢和血管生成中的关键作用，我们将SK作为开发糖尿病视网膜病变治疗新药的创新分子靶点。鞘脂被越来越多地认为是细胞凋亡、应激反应、细胞分化和增殖的关键介质，并且已知与糖尿病视网膜病变中至关重要的血管生成级联中的关键参与者相互作用。具体而言，由SK产生的鞘氨醇-1-磷酸（S1 P）介导血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）和蛋白激酶C（PKC）的作用，所有这些在糖尿病视网膜病变的表现中具有关键作用。因此，SK是开发用于该疾病的新治疗剂的关键分子靶标。 尽管有越来越多的证据表明SK在调节增殖和血管生成中具有关键作用，但SK的药理学抑制是治疗基于血管生成的疾病如糖尿病视网膜病变的未经测试的手段。这主要是由于迄今为止缺乏非常有用的SK抑制剂。为了克服这个问题，我们最近发现了新的抑制剂的人SK。我们假设，这些SK抑制剂将是有用的，以阻止有害的血管生成的VEGF和bFGF的影响，从而改善糖尿病视网膜病变。为了提供这些化合物效用的原理验证评价，本项目第I阶段将讨论以下具体目标： 1）。合成足够量的三种SK抑制剂用于体外和体内研究。 2）。确定这些SK抑制剂对VEGF和bFGF介导的促进血管生成的信号级联的体外作用。 3）。评价SK抑制剂在两种糖尿病视网膜病变啮齿动物模型中的体内毒性和治疗效果。 由于我们之前的工作导致了这些化合物的鉴定和合成方法的开发，以及我们的顾问在糖尿病视网膜病变模型方面的专业知识，我们目前处于独特的位置来进行拟议的研究。