Prolonged Inhibition of Pathologic Neovascularization by Catalytic Antioxidants

催化抗氧化剂对病理性新血管形成的长期抑制

• 批准号: 8798665
• 负责人: JAMES Francis MCGINNIS
• 金额: $ 53.75万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8798665
• 关键词: Acute; Age related macular degeneration; Animals; Antioxidants; Basic Science; Blindness; Blood; Blood Vessels; Cells; Cerium; Chronic; Clinical Research; Confocal Microscopy; Data; Development; Diabetic Retinopathy; Disease; Economic Burden; Effectiveness; Electroretinography; Enzymes; Epithelial; Extravasation; Eye diseases; Gene Expression; Gene Proteins; Genes; Goals; Health; Hypoxia; Inductively Coupled Plasma Mass Spectrometry; Inflammation; Intercellular Junctions; Knockout Mice; Knowledge; Lesion; Liquid substance; Longevity; Longitudinal Studies; Macular degeneration; Mus; Nuclear; Optical Coherence Tomography; Outcome; Oxidative Stress; Pathologic; Pathologic Neovascularization; Pathology; Patients; Phase; Photoreceptors; Production; Publishing; Quality of life; Reactive Oxygen Species; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Edemas; Retinal Neovascularization; Retinal Pigments; Structure of retinal pigment epithelium; Sulforaphane; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Thick; Time; VLDL receptor; Vascular Endothelial Growth Factors; Vision; Western Blotting; Work; angiogenesis; antioxidant enzyme; base; cerium oxide nanoparticle; combinatorial; cost; improved; in vivo; inherited retinal degeneration; neovascular; neovascularization; particle; prevent; proliferative diabetic retinopathy; protein structure; regenerative; research study; therapeutic target

DESCRIPTION (provided by applicant): In some forms of Diabetic Retinopathy (DR) and Macular Degeneration (AMD), blindness results from the pathologic development of new blood vessels which are incomplete, weak and porous. The progression of these neovascular diseases is thought to occur through the production of toxic molecules, Reactive Oxygen Species (ROS). There are no long term successful therapies for such diseases which have devastating effects on patients and cost the USA over $50 billion/yr. Our long term goal is to develop a therapeutic treatment to protect the health and function of retinal cells and thereby prolong vision and improve the quality of life for patients with DR or AMD. Because the excessive rise in ROS occurs "upstream" of most other retinal pathologies, it represents a common node which can be targeted by antioxidants and other molecules which increase the expression of "Phase II" antioxidant enzymes. Our published and preliminary data show that cerium oxide nanoparticles, which catalytically destroy ROS, can prevent development of pathologic choroidal and retinal neovascular lesions and cause the regression of existing pathologic neovessels in the Very Low Density Lipoprotein Receptor null retina by modulating the expression of many retinal genes including Vascular Endothelial Growth Factor (VEGF). Our central hypothesis is that cerium oxide nanoparticles, because of their catalytic antioxidant activity and long term retention in the retina, will continuously scavenge ROS and inhibit pathologic neovascularization over prolonged times -up to 12 months. Specific aim 1 will determine duration of nanoceria in the retina and the extent to which they retain activity against neovascularization. Inductively coupled plasma mass spectrometry will quantitate cerium at the parts per billion levels. Fundoscopy, electroretinography and optical coherence tomography will be used for longitudinal studies on the same animal to evaluate neovascularization, retinal function and thickness of the outer nuclear layer. Nanoceria effects on specific genes involved in oxidative stress, inflammation and neovascularization will be analyzed using confocal microscopy, Western blots and PCR arrays. Specific Aim 2 will demonstrate that nanoceria provide protection to the retina by reducing the effects of oxidative stress on photoreceptors and Retinal Pigment Epithelial (RPE) cells. Gene activity, proteins and structures indicative of photoreceptor- and/or RPE- oxidative stress will be evaluated. Specific Aim 3 will test the hypothesis that the combinatorial use of nanoceria and sulforaphane, an inducer of Phase II antioxidant enzymes, will result in an additive or synergistic effects in the Vldlr retina. Expected outcomes - the work proposed is expected to demonstrate the longevity, potency and mechanisms by which nanoceria inhibit pathologic neovascularization in the retina. The results are expected to have an important positive impact because the demonstration of the long term effectiveness of the nanoceria will most likely support their therapeutic use and changes in activity of identified genes should provide additional targets important for treating DR, AMD and other diseases which involve oxidative stress.

描述（由申请人提供）：在某些形式的糖尿病视网膜病变（DR）和黄斑变性（AMD）中，失明是由于不完整、脆弱和多孔的新血管的病理发育造成的。这些新生血管疾病的进展被认为是通过有毒分子活性氧（ROS）的产生而发生的。此类疾病尚无长期成功的治疗方法，这些疾病对患者造成毁灭性影响，美国每年花费超过 500 亿美元。我们的长期目标是开发一种治疗方法来保护视网膜细胞的健康和功能，从而延长 DR 或 AMD 患者的视力并提高生活质量。由于 ROS 的过度升高发生在大多数其他视网膜病变的“上游”，因此它代表了一个共同的节点，可以作为抗氧化剂和其他分子的目标，从而增加“第二阶段”抗氧化酶的表达。我们已发表的初步数据表明，氧化铈纳米粒子可催化破坏ROS，可以防止病理性脉络膜和视网膜新生血管病变的发展，并通过调节包括血管内皮生长因子（VEGF）在内的许多视网膜基因的表达，导致极低密度脂蛋白受体无效视网膜中现有病理性新生血管的消退。我们的中心假设是，氧化铈纳米颗粒由于其催化抗氧化活性和在视网膜中的长期保留，将持续清除 ROS 并在较长时间内（长达 12 个月）抑制病理性新生血管形成。具体目标 1 将确定纳米细胞在视网膜中的持续时间以及它们保留抗新生血管活性的程度。电感耦合等离子体质谱法可对铈进行十亿分之几的定量。眼底镜检查、视网膜电图检查和光学相干断层扫描将用于对同一动物进行纵向研究，以评估新生血管形成、视网膜功能和外核层厚度。将使用共聚焦显微镜、蛋白质印迹和 PCR 阵列分析 Nanoceria 对涉及氧化应激、炎症和新血管形成的特定基因的影响。具体目标 2 将证明纳米陶瓷通过减少氧化应激对光感受器和视网膜色素上皮 (RPE) 细胞的影响来保护视网膜。将评估指示光感受器和/或RPE-氧化应激的基因活性、蛋白质和结构。具体目标 3 将测试以下假设：纳米陶瓷和萝卜硫素（II 期抗氧化酶的诱导剂）的组合使用将在 Vldlr 视网膜中产生相加或协同效应。预期结果——所提出的工作预计将证明纳米陶瓷抑制视网膜病理性新生血管的寿命、效力和机制。预计结果将产生重要的积极影响，因为纳米陶瓷的长期有效性的证明很可能支持其治疗用途，并且已识别基因活性的变化应该为治疗 DR、AMD 和其他涉及氧化应激的疾病提供重要的额外靶标。

项目成果

Understanding the adsorption interface of polyelectrolyte coating on redox active nanoparticles using soft particle electrokinetics and its biological activity.

• DOI: 10.1021/am405250g
• 发表时间: 2014-04-23
• 期刊: ACS APPLIED MATERIALS & INTERFACES
• 影响因子: 9.5
• 作者: Saraf, Shashank;Neal, Craig J.;Das, Soumen;Barkam, Swetha;McCormack, Rameech;Seal, Sudipta
• 通讯作者: Seal, Sudipta