Reversing Contractility in Epiretinal Membranes

逆转视网膜前膜的收缩性

• 批准号: 10608051
• 负责人: Timothy A. Blenkinsop
• 金额: $ 42.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608051
• 关键词: Adult; Affect; Age related macular degeneration; Amendment; Animal Model; Blindness; Cartilage; Cell Culture Techniques; Cells; Contracts; Creativeness; Data; Disabled Persons; Disease; Disease Progression; Elements; Endothelial Cells; Epigenetic Process; Epiretinal Membrane; Eye diseases; Fatty acid glycerol esters; Fostering; Functional disorder; Future; Gene Expression; Genes; Genetic Transcription; Goals; Grant; Growth; Health protection; In Vitro; Knowledge; MADH3 gene; Macrophage; Mediating; Membrane; Mesenchymal; Methods; Mission; Modeling; Molecular Biology; Muller' s cell; Muscle; Muscle Cells; Muscle Contraction; Myofibroblast; Neuroglia; Outcome; Patients; Pericytes; Persons; Phenotype; Physiology; Population; Prevention; Proliferative Vitreoretinopathy; Proto-Oncogene Proteins c-akt; Protocols documentation; Public Health; RNA; Research; Research Proposals; Retina; Retinal Detachment; Retinal Diseases; Retinal Hemorrhage; Retinal Perforations; Retinitis Pigmentosa; Role; Severities; Signal Pathway; Signal Transduction; Structure of retinal pigment epithelium; TNF gene; Techniques; Testing; Tissue membrane; Transforming Growth Factor beta; United States National Institutes of Health; Vision; Work; bone; cell transformation; cell type; design; experimental study; in vitro Model; in vivo Model; innovation; insight; macula; membrane model; novel; novel strategies; novel therapeutic intervention; p38 Mitogen Activated Protein Kinase; preservation; prevent; proliferative diabetic retinopathy; response to injury; stem-like cell; therapy development; transcription factor; transcriptome; transcriptome sequencing; whole genome

While much is known on the causes of epiretinal membrane formation in retina diseases such as Proliferative Vitreoretinopathy (PVR) and Proliferative Diabetic Retinopathy (PDR), the progression of cell transformation into myocontractile phenotype and the machinery responsible for the contraction is less understood. The long-term goal is that when a membrane in patients with Proliferative Vitreoretinopathy or Proliferative Diabetic Retinopathy is identified we have an understanding of the contraction machinery responsible and can prescribe treatments to stop or reverse membrane contraction. The objective of this proposal is to determine the components of the contraction machinery that are essential for membrane contraction. The central hypothesis is contraction associated genes we identify during whole transcriptome sequencing of patient epiretinal membranes are components of the contraction machinery are responsible for membrane contraction and retinal detachment in patients with PVR and PDR. The rational underlying this proposal is that completion will identify key physical targets that when disabled will prevent or reverse membrane contraction. The central hypothesis will be tested by pursuing two specific aims: 1) To determine the mechanisms underlying the transformation of retinal pigment epithelium (RPE) into a contracting membrane. 2) To identify contraction-associated genes in the membranes from patients with PVR and PDR and evaluate their necessity for contraction by retinal cells in a new model of membrane contraction and a well established animal model. We will pursue these aims using an innovative combination of analytical and manipulative techniques. These include using the protocol we designed to isolate RNA from patient dissected membranes with sufficient yield and quality enabling whole transcriptome sequencing. Additionally we will use retina cell culture methods and a new model of contraction developed by this team that enables the preservation of native physiology and resembles the disease contraction phenotype. We will use these new methods in tandem with well-established techniques in molecular biology. The research proposal is significant, because the results will identify the machinery responsible for retinal membrane contraction and vision loss in PVR and PDR. From this understanding, new therapeutic approaches may be developed for rescuing patients from vision loss. The expected outcome of this work is a more complete understanding of retinal membrane formation and contraction in two devastating eye diseases, which will provide insight into other fibrotic membrane diseases of the retina. The results will have a positive impact immediately as the new knowledge gained will point to new targets for the prevention of vision loss.

虽然在视网膜疾病（例如 增生性玻璃体病（PVR）和增殖性糖尿病性视网膜病（PDR），进展 细胞转化为肌收集表型和负责的机械 收缩不太了解。长期目标是当患者患者的膜 鉴定出我们有一个增生性玻璃体病变或增生性糖尿病性视网膜病变。 了解负责收缩机械的理解，并可以开处方以停止或 反向膜收缩。该提案的目的是确定 收缩机制对于膜收缩至关重要。中心假设是 我们在患者的整个转录组测序过程中鉴定的收缩相关基因 前膜是收缩机械的组成部分，负责膜 PVR和PDR患者的收缩和视网膜脱离。理性的基础 建议是完成将确定关键的物理目标，而在禁用时将预防或 反向膜收缩。中央假设将通过追求两个具体目标来检验： 1）确定视网膜色素上皮转化（RPE）的基础机制 进入收缩膜。 2）从膜中鉴定与收缩相关的基因 PVR和PDR的患者评估了视网膜细胞收缩的必要性 膜收缩和建立良好的动物模型的模型。我们将使用这些目标 分析和操纵技术的创新组合。这些包括使用 我们设计的协议是为了将RNA从患者解剖的膜中分离出足够的产量和 质量可以实现整个转录组测序。另外，我们将使用视网膜细胞培养 该团队开发的方法和新的收缩模型，可以保存 天然生理学并类似于疾病收缩表型。我们将在 与分子生物学方面的完善技术相连。研究建议很重要， 因为结果将确定负责视网膜膜收缩和 PVR和PDR的视力丧失。从这种理解中，可以开发出新的治疗方法 为了使患者免于视力丧失。这项工作的预期结果更完整 了解两种毁灭性眼部疾病的视网膜膜形成和收缩 将洞悉视网膜的其他纤维化膜疾病。结果将有一个 随着获得的新知识将指出新目标的积极影响 预防视力丧失。