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The role of Injury signals in RPE Reprogramming

损伤信号在 RPE 重编程中的作用

基本信息

批准号：
9902450
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902450
关键词：
Age related macular degeneration Animal Model Antioxidants Back Biological Models Blindness Cells Chick Embryo Complement Complement 3a Complement 5a Coupled Cysteine Data Diabetic Retinopathy Disease Embryo Epigenetic Process Epithelial Epithelium Excision Exhibits Eye FGF2 gene Fibroblast Growth Factor Genes Genetic Glaucoma Goals Growth Factor 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 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 regenerative regenerative therapy relating to nervous system repaired retinal damage retinal neuron retinal regeneration small molecule stem stem cells tissue regeneration transcriptome sequencing transdifferentiation

项目摘要

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.

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcriptome Profiling of Embryonic Retinal Pigment Epithelium Reprogramming.

DOI：
10.3390/genes12060840
发表时间：
2021-05-29
期刊：
Genes
影响因子：
3.5
作者：
Tangeman JA;Luz-Madrigal A;Sreeskandarajan S;Grajales-Esquivel E;Liu L;Liang C;Tsonis PA;Del Rio-Tsonis K
通讯作者：
Del Rio-Tsonis K

A biochemical basis for induction of retina regeneration by antioxidants.

DOI：
10.1016/j.ydbio.2017.08.013
发表时间：
2018-01-15
期刊：
Developmental biology
影响因子：
2.7
作者：
Echeverri-Ruiz N;Haynes T;Landers J;Woods J;Gemma MJ;Hughes M;Del Rio-Tsonis K
通讯作者：
Del Rio-Tsonis K

A Stage-Specific OTX2 Regulatory Network and Maturation-Associated Gene Programs Are Inherent Barriers to RPE Neural Competency.

DOI：
10.3389/fcell.2022.875155
发表时间：
2022
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
通讯作者：

DNA demethylation is a driver for chick retina regeneration.

DOI：
10.1080/15592294.2020.1747742
发表时间：
2020-09
期刊：
Epigenetics
影响因子：
3.7
作者：
Luz-Madrigal A;Grajales-Esquivel E;Tangeman J;Kosse S;Liu L;Wang K;Fausey A;Liang C;Tsonis PA;Del Rio-Tsonis K
通讯作者：
Del Rio-Tsonis K

Generation of a Retina Reporter hiPSC Line to Label Progenitor, Ganglion, and Photoreceptor Cell Types