Dyslipidemia and Diabetic Retinopathy

 描述(申请人提供)：糖尿病视网膜病变(DR)是一种威胁视力的疾病，几乎没有治疗选择。视网膜的轻度慢性炎症[1-8]和由于骨髓(BM)来源的循环血管生成细胞(CACs)功能受损而导致的血管修复不足[9-12]导致视网膜血管病变的进展。许多高血糖和血脂异常激活的途径促进了促炎症细胞因子、促炎性脂质和促血管生成因子的增加，从而导致视网膜内皮细胞和CAC功能障碍[2-4，6，9，10，13-25]。这些通路的失调被假设与microRNAs(MiRNAs)有关。这些小的非编码RNA不能完全适应目标基因，同时控制翻译和转录[26]。一些miRNA类别已被证明有助于糖尿病和糖尿病并发症[27，28]，包括糖尿病视网膜病变[29]。上一次资助期间的研究确定miR-15a是促炎和促血管生成途径的关键调节因子。MIR-15a通过直接结合和抑制鞘磷脂途径中的中心酶、酸性鞘磷脂酶(ASM)和抑制血管内皮生长因子-A(VEGF-A)来完成这些任务。基于这些数据，我们假设miRNAs通过同时调节视网膜和CACs中的促炎和促血管生成途径来代表预防和治疗DR的治疗靶点。我们将讨论miR-15a在DR中的作用，具体目标如下。具体目的1：验证糖尿病患者miR-15a表达减少导致ASM活性增加和血管内皮生长因子-A产生增加，从而导致视网膜前炎性改变、通透性增加和内皮功能障碍的假说。特定目的2：验证糖尿病患者miR-15a减少导致ASM激活和神经酰胺产生导致骨髓源性CACs膜流动性降低的假说。膜流动性降低会导致祖细胞被困在骨髓中，并由于迁移和外渗能力受损而降低修复功能。通过直接调节糖尿病视网膜和BM中ASM和VEGF-A的产生，操纵miR-15a同时控制鞘磷脂代谢和促血管生成途径，将提供一种独特而有效的“联合治疗”方法，将增加糖尿病视网膜病变药物治疗的药理武器。

 DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is a sight threatening disease with few therapeutic options. Low-grade chronic inflammation in the retina [1-8] and inadequate vascular repair due to compromised function of the bone marrow (BM)-derived circulating angiogenic cells (CACs) [9-12] contribute to progression of retinal vascular pathology. A number of hyperglycemia- and dyslipidemia- activated pathways promoting the increase of pro-inflammatory cytokines, pro-inflammatory lipids and pro-angiogenic factors leading to retinal endothelial cell and CAC dysfunction have been identified [2-4, 6, 9, 10, 13-25]. Dysregulation of these pathways is hypothesized to involve microRNAs (miRNAs). These small non-coding RNAs anneal imperfectly to target genes and simultaneously control translation and transcription [26]. Several miRNA classes have been shown to contribute to diabetes and diabetic complications [27, 28], including diabetic retinopathy [29]. Studies during the previous funding period identified miR-15a as a key regulator of both pro-inflammatory and pro-angiogenic pathways. miR-15a accomplishes these tasks through direct binding and inhibition of the central enzyme in the sphingolipid pathway, acid sphingomyelinase (ASM), and inhibition of VEGF-A. Based on these data, we hypothesize that miRNAs represent therapeutic targets for prevention and treatment of DR by simultaneously regulating pro-inflammatory and pro-angiogenic pathways in the retina and CACs. We will address the role of miR-15a in DR with the following Specific Aims. Specific aim 1: To test the hypothesis that the decrease in miR-15a observed in diabetes contributes to increased ASM activity and VEGF-A production leading to pro- inflammatory changes, increased permeability and endothelial dysfunction in the retina. Specific aim 2: To test the hypothesis that decrease in miR-15a in diabetes leads to ASM activation and ceramide production resulting in decreased membrane fluidity of bone marrow-derived CACs. Decreased membrane fluidity results in entrapment of progenitor cell in the bone marrow and reduced repair function due to impaired migration and extravasation capacity. Manipulation of miR-15a to simultaneously control sphingolipid metabolism and pro-angiogenic pathways through direct regulation of ASM and VEGF-A production in the diabetic retina and BM should provide a unique and effective "combination therapy" approach that will add to the pharmacological armamentarium of drug therapies for diabetic retinopathy.