Dyslipidemia and Diabetic Retinopathy

 描述（由申请人提供）：糖尿病视网膜病变（DR）是一种威胁视力的疾病，治疗选择很少。视网膜中的低度慢性炎症[1-8]和由于骨髓（BM）衍生的循环血管生成细胞（CAC）的功能受损而导致的血管修复不足[9-12]有助于视网膜血管病理学的进展。已经确定了许多高血糖和血脂异常激活的途径，这些途径促进促炎细胞因子、促炎脂质和促血管生成因子的增加，导致视网膜内皮细胞和CAC功能障碍[2-4，6，9，10，13-25]。这些途径的失调被假设涉及microRNAs（miRNAs）。这些小的非编码RNA与靶基因不完全退火，同时控制翻译和转录[26]。几种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]。上一个资助期的研究将miR-15 a确定为促炎症和促血管生成途径的关键调节因子。miR-15 a通过直接结合和抑制鞘脂途径中的中心酶酸性鞘磷脂酶（ASM）以及抑制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，代表了预防和治疗DR的治疗靶点。我们将通过以下具体目标来解决miR-15 a在DR中的作用。具体目标1：为了检验在糖尿病中观察到的miR-15 a减少有助于增加ASM活性和VEGF-A产生，从而导致视网膜中的促炎性变化、增加的渗透性和内皮功能障碍的假设。具体目标2：检验糖尿病中miR-15 a减少导致ASM活化和神经酰胺产生，从而导致骨髓源性CAC膜流动性降低的假设。膜流动性降低导致祖细胞滞留在骨髓中，并由于迁移和外渗能力受损而导致修复功能降低。通过直接调节糖尿病视网膜和BM中ASM和VEGF-A的产生来操纵miR-15 a以同时控制鞘脂代谢和促血管生成途径，这将提供独特且有效的“组合疗法”方法，其将增加糖尿病视网膜病变的药物疗法的药理学设备。

 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.