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Amelioration of Uveitis by Aldose reductase Inhibition

通过抑制醛糖还原酶来改善葡萄膜炎

基本信息

批准号：
7895590
负责人：
KOTA VENKATA RAMANA
金额：
$ 37.75万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895590
关键词：
Accounting Adverse effects Affect Aldehyde Reductase Aldehydes Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Aqueous Humor Attenuated Autoimmune Diseases Autoimmune Process Autoimmunity Bacterial Infections Blindness Blood Vessels CCL2 gene Carrier Proteins Cattle Cell Adhesion Molecules Cell Culture Techniques Cell Line Cell physiology Cells Chronic Clinic Clinical Trials Complication Data Developing Countries Development Diabetes Mellitus Diabetic Neuropathies Dinoprostone Disease Dose E-Selectin Endocrinology Endotoxins Enzymes Epithelial Cells Etiology Extravasation Eye Foundations Functional disorder Future Glutathione Goals Growth Factor Health Services Accessibility Homeostasis Human Hyperglycemia Immune response Immune system In Vitro Incidence Infection Infiltration Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Intercellular adhesion molecule 1 Interleukin-1 Interleukin-12 Interleukin-17 Interleukin-6 Investigation Knockout Mice Leukocytes Leukostasis Light Lipid Peroxidation Lipids Lipopolysaccharides Lymphocyte Macrophage Inflammatory Protein-1 Measures Mediating Mediator of activation protein Metabolic Metabolism Methods Modeling Molecular Molecular Target Monitor Mus NADPH Oxidase Na(+)-K(+)-Exchanging ATPase Nitric Oxide Normal tissue morphology Oxidation-Reduction Oxidative Stress Participant Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Phase Play Positioning Attribute Production Property Proteins Publishing Quality of life Rattus Reactive Oxygen Species Regulation Reporting Retinal Risk Risk Factors Rodent Model Role Serum Severities Signal Pathway Signal Transduction Small Interfering RNA Steroids Subcutaneous Injections Symptoms Testing Therapeutic Tissues Transcription Factor AP-1 Uvea Uveitis Vimentin Vision Visual impairment Vitreous Chamber activating transcription factor adduct autocrine base chemokine cyclooxygenase 2 cytokine cytotoxic cytotoxicity diabetic diabetic rat experience fidarestat human NOS2A protein in vivo inflammatory marker inhibitor/antagonist innovation interstitial retinol-binding protein lens macrophage mouse model non-diabetic novel novel therapeutic intervention paracrine prevent receptor transcription factor

项目摘要

Uveitis, an ocular inflammatory disease of unknown etiology, is a major complication during autoimmune disorders and infections and is associated with severe visual impairment. Uveitis may result from direct involvement of the uveal tract or indirect inflammation of adjacent eye tissues. Inflammation is an example of cytotoxicity caused by the formation of reactive oxygen species (ROS)-sensitive NF-KB dependent inflammatory cytokines and chemokines, and their autocrine and paracrine effects. However, the mechanisms through which increased ROS and inflammatory markers cause ocular inflammation are not well understood. Our recent studies have shown that aldose reductase (AR), which catalyzes the reduction of lipid peroxidation-generated lipid derived aldehydes (LDAs) and their glutathione conjugates, is an obligatory mediator of cytokine, chemokine, growth factor -induced activation of NF-KB and AP1 via PLC/PKC/IKKIMAPK in various cell lines including human lens epithelial cells (HLECs) and macrophages. We have also shown that AR inhibition prevents bacterial endotoxin (LPS)-induced production of inflammatory markers such as nitric oxide, TNF-a, PGE2 and Cox-2 in HLECs as well as in rat eyes. Our preliminary studies also suggest that AR inhibition prevents endotoxin and autoimmune-induced uveitis in rats. Therefore, our long-term goal is to understand the mechanisms by which AR contributes to ocular inflammation, and to use AR inhibitors to prevent uveitis and its associated complications in non-diabetics and diabetes. We will now systematically test our central hypothesis "that AR's catalytical activity plays a pivotal role in the transduction of ROS -induced inflammatory response leading to uveitis" by investigating the role of AR in mediating LPS-induced inflammatory response in cultured ocular epithelial cells as well as rodent models of uveitis.

葡萄膜炎是一种病因不明的眼部炎症性疾病，是自身免疫性疾病和感染期间的主要并发症，并与严重的视力障碍有关。葡萄膜炎可能由葡萄膜的直接受累或邻近眼组织的间接炎症引起。炎症是由活性氧 (ROS) 敏感的 NF-KB 依赖性炎症细胞因子和趋化因子的形成及其自分泌和旁分泌作用引起的细胞毒性的一个例子。然而，ROS 和炎症标志物增加导致眼部炎症的机制尚不清楚。很好理解。我们最近的研究表明，醛糖还原酶 (AR) 可催化脂质过氧化产生的脂质衍生醛 (LDA) 及其谷胱甘肽缀合物的还原，是细胞因子、趋化因子、生长因子通过 PLC/PKC/IKKIMAPK 诱导的各种细胞系（包括人类）激活 NF-KB 和 AP1 的必需介质。晶状体上皮细胞（HLEC）和巨噬细胞。我们还表明，AR 抑制可防止 HLEC 以及大鼠眼中细菌内毒素 (LPS) 诱导的炎症标记物（例如一氧化氮、TNF-a、PGE2 和 Cox-2）的产生。我们的初步研究还表明，AR 抑制可预防内毒素和自身免疫诱发的大鼠葡萄膜炎。因此，我们的长期目标是了解 AR 导致眼部炎症的机制，并使用 AR 抑制剂来预防非糖尿病和糖尿病患者的葡萄膜炎及其相关并发症。我们现在将系统地检验我们的中心假设“AR 的催化活性发挥着通过研究 AR 在介导培养的眼上皮细胞和啮齿动物葡萄膜炎模型中 LPS 诱导的炎症反应中的作用，“在 ROS 诱导的炎症反应导致葡萄膜炎的转导中发挥关键作用”。