The role of Injury signals in RPE Reprogramming

损伤信号在 RPE 重编程中的作用

• 批准号: 9129196
• 负责人: Katia Del Rio-Tsonis
• 金额: $ 36.13万
• 依托单位: MIAMI UNIVERSITY OXFORD
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129196
• 关键词: Age related macular degeneration; Animal Model; Antioxidants; Back; Biological Models; Blindness; Cells; Chick Embryo; Complement; Complement 3a; Complement 5a; Cysteine; Data; Diabetic Retinopathy; Disease; Embryo; Epigenetic Process; Epithelial; Epithelium; Excision; Exhibits; Eye; FGF2 gene; Fibroblast Growth Factor; Figs - dietary; Gene Targeting; Genes; Genetic; Glaucoma; Goals; Growth; Human; Inflammation; Injury; Interleukin-6; Knowledge; Lead; MAP Kinase Gene; Mammals; Mesenchymal; Molecular; Natural regeneration; Neural Retina; Neurons; Outcome; Oxidation-Reduction; Pathway interactions; Phase; Play; Process; Proliferating; Publishing; Reactive Oxygen Species; Regenerative Medicine; Research; Retina; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; Structure of retinal pigment epithelium; Testing; Up-Regulation; Vision; Visual impairment; Visual system structure; Work; cell type; cytokine; injured; innovation; methylome; neuroepithelium; neuron loss; public health relevance; receptor coupling; regenerative; regenerative therapy; relating to nervous system; repaired; retinal neuron; small molecule; stem; tissue regeneration; transcriptome sequencing; transdifferentiation

 DESCRIPTION (provided by applicant): The leading causes of blindness and low vision in the US include AMD, diabetic retinopathy and glaucoma. Current therapies offer few options to those suffering from late stages of these diseases. In order to explore possible therapies, it is important to use animal models with regenerative capabilities such as the chick embryo. Embryonic chicks regenerate their retina, following retinectomy, by reprogramming the remaining retinal pigmented epithelium (RPE) as long as an inducing factor is present. This reprogramming process allows the RPE to dedifferentiate, proliferate and form a neuro-epithelium that eventually differentiates generating retina. The process of dedifferentiation is ke to understanding how RPE reprogramming works. RPE reprogramming utilizes a two-step dedifferentiation process where injury (retinectomy) stimulates the RPE to become competent to respond to inducing factors. We have identified several inducing factors that are able to reprogram the RPE to neural retina, however, the role for these molecules in RPE reprogramming remains unknown. In this proposal we will dissect the mechanisms by which inducing factors such complement components C3a, C5a and inflammation associated molecules including IL-6 and antioxidant N-acetyl cysteine (NAC) reprogram the RPE. Specifically, we will explore if these factors/molecules exhibit interdependence, if they require common signaling pathways or if they regulate common target genes using similar or distinct epigenetic strategies. We will test the following hypothesis: Inducing factors direct RPE reprogramming and retina regeneration by initiating downstream signaling cascades such as MAPK, PI3K, Wnt and/or Jak/Stat pathways commonly activated by growth factor and G-coupled receptors. Through these pathways, the inducing factors epigenetically control common genes that regulate RPE reprogramming. The urgency for restoring vision lead the NEI to announce an audacious goal "to restore vision through regeneration of neurons and neural connections in the eye and visual system". This study provides a model system where to test small molecules such as C3a, C5a, IL-6 and NAC to evaluate induction of retina regeneration and a platform where to dissect the cellular and molecular mechanisms involved in this process. This work will have a significant impact on the field of regenerative medicine since the information obtained can be extrapolated to the process of retina repair in mammals including humans, and specifically on the potential reprogramming of human RPE to generate new neurons.

 描述（由申请人提供）：在美国，失明和低视力的主要原因包括AMD、糖尿病性视网膜病变和青光眼。目前的治疗方法为患有这些疾病的晚期患者提供的选择很少。使用具有再生能力的动物模型（例如雏鸡胚胎）在视网膜切除后通过重新编程剩余的视网膜色素上皮来再生视网膜非常重要。 (RPE) 只要存在诱导因子，该重编程过程就可以使 RPE 去分化、增殖并形成神经上皮，最终分化生成视网膜。去分化过程有助于了解 RPE 重编程如何发挥作用。一个两步去分化过程，其中损伤（视网膜切除术）刺激 RPE 变得有能力对诱导因素做出反应。我们已经确定了几种能够重新编程的诱导因素。然而，这些分子在 RPE 重编程中的作用仍然未知。在本提案中，我们将剖析补体成分 C3a、C5a 和炎症相关分子（包括 IL-6 和抗氧化剂 N-乙酰半胱氨酸）等诱导因子的机制。 (NAC) 重新编程 RPE。具体来说，我们将探讨这些因子/分子是否表现出相互依赖性，它们是否需要共同的信号通路，或者它们是否使用相似或不同的表观遗传策略来调节共同的靶基因。假设：诱导因子通过启动通常由生长因子和 G 偶联受体激活的下游信号级联（例如 MAPK、PI3K、Wnt 和/或 Jak/Stat 通路）来指导 RPE 重编程和视网膜再生。通过这些通路，诱导因子在表观遗传上控制共同的作用。调节 RPE 重编程的基因使得恢复视力的紧迫性促使 NEI 宣布了一个大胆的目标“通过眼睛和眼睛中的神经元和神经连接的再生来恢复视力”。这项研究提供了一个模型系统，可以测试 C3a、C5a、IL-6 和 NAC 等小分子，以评估视网膜再生的诱导，并提供一个平台来剖析此过程中涉及的细胞和分子机制。这项工作将对再生医学领域产生重大影响，因为获得的信息可以推断到包括人类在内的哺乳动物的视网膜修复过程，特别是人类 RPE 的潜在重新编程以产生新的神经元。