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性视网膜病（DR）和黄斑变性（AMD）中，失明是由新血管的病理发育引起的，这些新血管不完整，弱且多孔。这些新血管疾病的进展被认为是通过产生有毒分子，活性氧（ROS）而发生的。对于此类疾病，对患者产生毁灭性影响，并使美国损失超过500亿美元/年，没有长期的成功疗法。我们的长期目标是开发一种治疗治疗，以保护视网膜细胞的健康和功能，从而延长视力并改善DR或AMD患者的生活质量。由于ROS中的过度上升发生在大多数其他视网膜病理中的“上游”，因此它代表了一个常见的节点，可以由抗氧化剂和其他分子靶向，这些节点增加了“ II期”抗氧化剂酶的表达。我们发表的初步数据表明，催化破坏ROS的氧化葡萄纳米颗粒可以防止病理性脉络膜和视网膜新血管病变的发展，并在非常低密度的脂蛋白受体无效的视网膜中导致现有病理神经的回归，包括许多视网膜基因的表达（包括许多视网膜杂质）（包括许多视网膜杂质）。我们的中心假设是，氧化岩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，将在长时间至12个月内连续清除ROS并抑制病理新生血管化。具体的目标1将确定视网膜中纳米钙的持续时间及其对新血管形成的活性的程度。电感耦合的等离子体质谱法将以十亿级的零件定量元素。基础镜检查，电视图和光学相干断层扫描将用于对同一动物的纵向研究，以评估外部核层的新血管形成，视网膜功能和厚度。将使用共聚焦显微镜，蛋白质印迹和PCR阵列分析纳米症对参与氧化应激，炎症和新血管形成的特定基因的影响。特定的目标2将证明纳米症通过减少氧化应激对感光体和视网膜色素上皮（RPE）细胞的影响来为视网膜提供保护。将评估基因活性，蛋白质和结构，指示光感受器 - 和/或RPE-氧化应激。具体目标3将检验以下假设：II期抗氧化剂酶的纳米层和硫素的联合使用将导致VLDLR视网膜的加性或协同作用。预期的结果 - 预计所提出的工作将证明纳米果在视网膜中抑制病理新生血管形成的寿命，效力和机制。预计结果将产生重要的积极影响，因为纳米症的长期有效性的证明很可能会支持其治疗用途，并且鉴定基因活动的变化应为治疗涉及氧化应激的DR，AMD和其他疾病的其他靶标提供重要的目标。

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