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.

项目总结