Role of S100 proteins in Diabetic Retinopathy

S100 蛋白在糖尿病视网膜病变中的作用

• 批准号: 10666595
• 负责人: Shyam Sunder Chaurasia
• 金额: $ 36.22万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666595
• 关键词: Affect; Angiogenesis Inhibitors; Awareness; Basement membrane; Binding Proteins; Biological Assay; Blindness; Blood Vessels; Blood capillaries; Blood-Retinal Barrier; C-reactive protein; Calgranulin B; Cell physiology; Cells; Chronic; Clinical Research; Complex; Data; Defect; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Retinopathy; Diabetic mouse; Disease; Disease Progression; Dose; Dyslipidemias; Electroretinography; Endothelial Cells; Endothelium; Extravasation; Eye; Family; Family suidae; Fluorescein Angiography; Fundus; Fundus photography; Genes; Genetic Predisposition to Disease; Goals; Health Care Costs; Heart; Human; Hyperglycemia; In Vitro; Incidence; Inflammasome; Inflammation; Inflammatory; Injections; Interleukin-1 beta; Interleukin-6; Intervention; Joints; Kidney; Knockout Mice; Laser Surgery; Measurement; Metabolic syndrome; Microglia; Miniature Swine; Molecular; Molecular Target; Molecular Weight; Morbidity - disease rate; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ophthalmologist; Optical Coherence Tomography; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Pericytes; Persons; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Population; Prediabetes syndrome; Proteins; Public Health; Publications; Research Personnel; Retina; Rodent; Role; S100 Proteins; S100A8 gene; S100A9 gene; Serum; Signal Transduction; Sterility; Stress; Symptoms; TLR4 gene; TNF gene; Testing; Therapeutic; Thinness; Time; Tissues; Transgenic Organisms; Translational Research; Up-Regulation; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vision; Work; cellular targeting; chemokine; clinical examination; combat; cytokine; diabetic; diabetic patient; experience; experimental study; extracellular; gain of function; glycemic control; in vivo; in vivo Model; inhibitor; innovation; laser photocoagulation; loss of function; macular edema; metabolic abnormality assessment; mouse model; neovascularization; novel; novel therapeutics; overexpression; pharmacologic; porcine model; proliferative diabetic retinopathy; retinal damage; retinal neuron; skills; small molecule inhibitor; time use; tool; western diet

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.

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， 全世界有100万糖尿病患者。糖尿病的发病率在世界范围内不断增加， 预计到2045年将达到约4.35亿人，因此发病率和医疗保健成本 预计与DR相关的疾病将升级，加剧本已严重的公共卫生问题。 问题. DR的一个重要问题是缺乏早期主观症状， 当他们意识到视力异常时，要扭转疾病进展为时已晚。 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 最终导致新血管形成。目前的治疗方法仅适用于晚期 DR阶段，其涉及眼内注射抗血管内皮生长因子（抗- VEGF）药物和外科激光介入。不幸的是，这些治疗是昂贵的， 需要多次注射，往往无法治疗每一个病人。 长期目标是确定新的VEGF非依赖性分子靶点，如S100 蛋白质，一个低分子量Ca2+结合蛋白家族，涉及多种 细胞内和细胞外功能。DR小鼠和猪模型的初步数据显示， 视网膜中S100A9蛋白的上调。这项提议测试了一个新的假设，即S100A9 蛋白质在糖尿病应激下由视网膜小胶质细胞释放，并被 在DR发病机制中，内皮细胞可加重炎症通路。通过三 提出的目标，我们将1）确定S100A9蛋白在视网膜小胶质细胞中的功能作用 研究S100A9在高血糖和血脂异常应激中的作用机制。 DR的发病机制;以及3）评估S100A9特异性小分子抑制剂帕喹莫德 用于DR进展的药物干预。这些研究将导致更好的 了解分子途径和一个潜在的新的目标，为干预DR。