Role of S100 proteins in Diabetic Retinopathy

摘要 糖尿病视网膜病变(DR)是一种神经退行性和微血管疾病，影响~93 全球有100万糖尿病患者。糖尿病的发病率在全球范围内呈上升趋势， 预计到2045年将达到约4.35亿，因此发病率和医疗成本 与DR相关的疾病预计将升级，加剧本已严重的公共健康 问题。 DR的一个重要问题是缺乏早期的主观症状，因此当患者 当他们意识到视力异常时，就来不及逆转疾病的发展了。 DR影响视网膜神经元组织和血-视网膜屏障的破坏，以及血管渗漏。 最终导致新生血管。目前的治疗方法仅适用于晚期 DR分期，包括眼内注射抗血管内皮生长因子(抗血管内皮生长因子) 血管内皮生长因子)药物和外科激光干预。不幸的是，这些治疗都很昂贵， 需要多次注射，往往无法治疗每一位患者。 长期目标是确定新的不依赖血管内皮生长因子的分子靶点，如S100 蛋白质，一个低分子量的钙结合蛋白家族，参与多种 细胞内和细胞外的功能。DR小鼠和猪模型的初步数据显示 S100A9蛋白在视网膜中的上调。这项提议检验了一种新的假设，即S100A9 蛋白质由糖尿病应激下的视网膜小胶质细胞释放，并由 内皮细胞在DR发病机制中加重炎症通路。到三个月 提出的目标是：1)确定S100A9蛋白在视网膜小胶质细胞中的功能 2)研究S100A9在高血糖和高脂血症应激中的作用机制。 DR的发病机制；3)评价S100A9特异性小分子抑制剂帕奎莫特 用于DR进展的药物干预。这些研究将导致更好的 对分子通路的理解和DR干预的潜在新靶点。

ABSTRACT Diabetic retinopathy (DR) is a neurodegenerative and microvascular disorder affecting ~93 million diabetic people worldwide. The incidence of diabetes is increasing worldwide and predicted to reach ~435 million by 2045, and hence the morbidity and healthcare costs associated with DR are predicted to escalate, exacerbating an already serious public health issue. A significant problem with DR is the lack of early subjective symptoms so that by the time patients become aware of an abnormality in their vision, it is too late to reverse the disease progression. DR affects retinal neuronal tissue and breakdown of blood-retina barrier, and vascular leakage eventually causing neovascularization. The current treatments are only applicable to advanced stages of DR, which involve intraocular injection of anti-vascular endothelial growth factor (anti- VEGF) drugs and surgical laser intervention. Unfortunately, these treatments are expensive, require multiple injections and often failed to treat every patient. The long-term goal is to identify new VEGF-independent molecular targets such as S100 proteins, a family of low-molecular weight Ca2+-binding proteins implicated in a variety of intracellular and extracellular functions. Preliminary data in DR mice and porcine models showed upregulation of S100A9 protein in the retina. This proposal tests a novel hypothesis that S100A9 protein is released by the retinal microglia cells under diabetic stress, and is taken up by the endothelial cells to exacerbate inflammatory pathways in DR pathogenesis. Through three proposed aims, we will 1) define the functional role of S100A9 protein in the retinal microglia under hyperglycemia and dyslipidemia stress; 2) study the mechanistic role of S100A9 in the pathogenesis of DR; and 3) evaluate the S100A9-specific small molecule inhibitor, paquinimod for the pharmacological intervention of DR progression. These studies will lead to a better understanding of the molecular pathways and a potential novel target for the intervention of DR.