Role of S100 proteins in Diabetic Retinopathy

S100 蛋白在糖尿病视网膜病变中的作用

基本信息

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
项目类别：
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

项目摘要

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.

抽象的糖尿病视网膜病变 (DR) 是一种神经退行性和微血管疾病，影响约 93 全球有 100 万糖尿病患者。糖尿病的发病率在全球范围内不断增加预计到 2045 年将达到约 4.35 亿，因此发病率和医疗费用预计与 DR 相关的风险将会升级，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，因此当患者当意识到视力异常时，要扭转疾病进展为时已晚。 DR 影响视网膜神经组织、血视网膜屏障破坏和血管渗漏最终导致新生血管形成。目前的治疗方法仅适用于晚期 DR 阶段，涉及眼内注射抗血管内皮生长因子（抗血管内皮生长因子） VEGF）药物和手术激光干预。不幸的是，这些治疗方法价格昂贵，需要多次注射，并且常常无法治疗每一位患者。长期目标是识别新的 VEGF 独立分子靶标，例如 S100 蛋白质，一类低分子量 Ca2+ 结合蛋白，与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。该提案测试了一个新假设：S100A9 蛋白质在糖尿病应激下由视网膜小胶质细胞释放，并被内皮细胞加剧 DR 发病机制中的炎症途径。通过三提出的目标，我们将 1) 定义 S100A9 蛋白在视网膜小胶质细胞中的功能作用高血糖和血脂异常压力下； 2）研究S100A9在 DR 的发病机制； 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。这些研究将带来更好的结果了解分子途径和干预 DR 的潜在新靶点。