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.

虽然对视网膜疾病中视网膜前膜形成的原因有很多了解， 增殖性玻璃体视网膜病变（PVR）和增殖性糖尿病视网膜病变（PDR）， 细胞转化为肌收缩表型的机制以及 收缩是不太了解的。长期的目标是，当患者的膜 糖尿病性视网膜病变是一种常见的视网膜病变， 了解负责的收缩机械，并可以规定治疗方法，以停止或 逆转膜收缩。本提案的目的是确定 收缩机制是膜收缩所必需的。核心假设是 我们在患者的全转录组测序过程中识别出收缩相关基因 视网膜前膜是收缩机制的组成部分，负责膜 PVR和PDR患者的收缩和视网膜脱离。这背后的理性 建议是，完成将确定关键的物理目标，当残疾人将防止或 逆转膜收缩。将通过追求两个具体目标来检验中心假设： 1)目的：探讨视网膜色素上皮细胞（RPE）转化的机制 收缩成一个膜。2)识别细胞膜中收缩相关基因 PVR和PDR患者，并评估他们在新的视网膜细胞收缩的必要性。 膜收缩模型和良好建立的动物模型。我们将通过以下方式实现这些目标： 分析和操纵技术的创新结合。其中包括使用 我们设计的方案是以足够的产率从患者解剖的膜中分离RNA， 高质量，可实现全转录组测序。此外，我们将使用视网膜细胞培养 方法和这个团队开发的新的收缩模型， 天然生理学和类似于疾病收缩表型。我们将使用这些新方法， 与成熟的分子生物学技术相结合。该研究项目意义重大， 因为结果将确定负责视网膜膜收缩的机制， PVR和PDR的视力丧失。从这一认识出发，可能会开发出新的治疗方法 拯救失明的病人这项工作的预期成果是一个更完整的 了解视网膜膜的形成和收缩在两个毁灭性的眼睛疾病， 将提供深入了解其他纤维化膜疾病的视网膜。结果将有一个 立即产生积极影响，因为获得的新知识将为 预防视力丧失。