Identification of novel therapeutic targets for age-related macular degeneration via a combined tissue engineering and systems biology approach

通过组织工程和系统生物学相结合的方法确定年龄相关性黄斑变性的新治疗靶点

• 批准号: 9181720
• 负责人: KRISTYN S MASTERS
• 金额: $ 24.29万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181720
• 关键词: 3-Dimensional; Acute; Address; Affect; Age related macular degeneration; Anatomy; Angiogenesis Inhibitors; Angiogenic Factor; Biological; Biology; Blindness; Blood; Blood Vessels; Bruch' s basal membrane structure; Cell Surface Receptors; Choroid; Choroidal Neovascularization; Coculture Techniques; Collagen; Complex; Computer Simulation; Development; Diffusion; Disease; Drug usage; Elderly; Elements; Endothelial Cells; Engineering; Environment; Epithelial; Experimental Models; Extracellular Matrix; Eye; FDA approved; Functional disorder; Gold; Growth; In Vitro; Individual; Lead; Ligands; Liquid substance; Lucentis; Modeling; Molecular; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Process; Property; Receptor Activation; Retina; Retinal; Retinal Pigments; Risk; Role; Staging; Structure; Structure of retinal pigment epithelium; System; Systems Biology; Testing; Time; Tissue Engineering; Tissues; Tubular formation; Vascular Endothelial Growth Factors; Work; alternative treatment; angiogenesis; cost; effective therapy; experience; glycation; in vitro Model; innovation; insight; neovascularization; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; ranibizumab; receptor; research study; response; treatment strategy

PROJECT SUMMARY Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, and results from inappropriate angiogenesis in the eye. As a result of this mechanism, anti-angiogenic drugs such as anti- vascular endothelial growth factor (VEGF) agents have become the preferred treatment for late-stage, or `wet', AMD. However, these drugs are accompanied by serious risks as they are injected repeatedly into the eye and over 50% of patients still experience vision loss. Unfortunately, the development of more effective therapies has been hampered by limited insight into the molecular mechanisms that promote angiogenesis in the retina. We hypothesize that the combined changes in the extracellular matrix (ECM) and retinal pigment epithelial (RPE) phenotype control angiogenesis in wet AMD. To test this, we propose to develop a tissue-engineered system that mimics several features of outer retinal anatomy and to then characterize angiogenesis in response to AMD-like changes to these features. This novel 3-D platform will allow us to uniquely address specific questions about retinal biology, yield information about the relative influences of retinal properties in regulating angiogenesis, and ultimately identify and screen new therapies for wet AMD. Aim 1: Create a tissue-engineered retinal environment to characterize the relative influences of AMD- mimicking changes on angiogenesis. We will develop a novel 3-D tissue-engineered system simulating key elements of the retinal anatomy. This system will be used to examine angiogenesis by endothelial cells (ECs) in the context of changes in the retinal microenvironment that mimic changes observed in wet AMD. Aim 2: Using a systems biology analysis, identify alternative targets or stage-specific treatments to regulate angiogenesis in AMD. We will utilize our tissue-engineered model to examine receptor activation on the ECs in response to angiogenic ligands secreted by RPE cells across different stages of angiogenesis. We will then use these experiments to construct a predictive computational model that will enable identification of individual (or combined) soluble factors that most strongly promote angiogenesis at various stages of disease. Via in silico perturbations, we will predict outcomes for inhibiting these factors/receptors, and then test these new inhibition strategies in our in vitro experimental model. The outcomes of this work will be: 1) creation of a sophisticated in vitro platform for characterizing the pathophysiology of wet AMD and relative contributions of microenvironmental factors in this process, 2) identification of novel targets and/or stage-specific treatments for wet AMD.

项目概要 年龄相关性黄斑变性 (AMD) 是发达国家失明的主要原因，其结果 来自眼睛不适当的血管生成。由于这种机制，抗血管生成药物如抗血管生成药物 血管内皮生长因子 (VEGF) 药物已成为晚期或“湿性”、 AMD。然而，这些药物由于反复注射入眼，存在严重的风险。 超过 50% 的患者仍然出现视力丧失。不幸的是，更有效的疗法的开发 由于对促进视网膜血管生成的分子机制的了解有限，该研究受到了阻碍。 我们假设细胞外基质（ECM）和视网膜色素上皮的综合变化 (RPE) 表型控制湿性 AMD 中的血管生成。为了测试这一点，我们建议开发一种组织工程 模拟外视网膜解剖结构的几个特征，然后表征血管生成的系统 响应类似 AMD 对这些功能的更改。这个新颖的 3D 平台将使我们能够独特地解决 有关视网膜生物学的具体问题，产生有关视网膜特性的相对影响的信息 调节血管生成，并最终识别和筛选湿性 AMD 的新疗法。 目标 1：创建组织工程视网膜环境来表征 AMD- 模仿血管生成的变化。我们将开发一种新颖的 3D 组织工程系统来模拟关键 视网膜解剖学的要素。该系统将用于检查内皮细胞（EC）的血管生成 视网膜微环境的变化模仿了湿性 AMD 中观察到的变化。 目标 2：利用系统生物学分析，确定替代靶标或针对特定阶段的治疗方法 调节 AMD 中的血管生成。我们将利用我们的组织工程模型来检查受体激活 ECs 对 RPE 细胞在血管生成的不同阶段分泌的血管生成配体做出反应。我们 然后将使用这些实验来构建一个预测计算模型，该模型将能够识别 在疾病的各个阶段最强烈地促进血管生成的单个（或组合）可溶性因子。 通过计算机扰动，我们将预测抑制这些因素/受体的结果，然后测试这些 我们的体外实验模型中的新抑制策略。 这项工作的成果将是：1）创建一个复杂的体外平台来表征 湿性 AMD 的病理生理学以及微环境因素在此过程中的相对贡献，2) 识别湿性 AMD 的新靶点和/或阶段特异性治疗方法。