Gene Therapy for Retinal Detachment

视网膜脱离的基因治疗

• 批准号: 6697449
• 负责人: JAMES J TOMASEK
• 金额: $ 14.65万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-16 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6697449
• 关键词: Gene; Therapy; Retinal; Detachment

DESCRIPTION (provided by applicant): Retinal detachment with subsequent loss of vision is a major clinical problem associated with a number of ocular diseases, including proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR). Surgery, the only treatment currently available, has a high rate of recurrence of fibrous epiretinal membrane formation and retinal detachment. Smooth muscle (SM) alpha-actin containing myofibroblasts are a major cell type present in the epiretinal membranes that form in PVR and PDR and it is these cells that are responsible for generation of force leading to retinal detachment. The long-term goal of this research is to develop a gene therapy-based approach that targets and blocks the contraction of the myofibroblast. The first objective of this project is to develop a myofibroblast-specific promoter. Recent studies have suggested that the regulation of SM alpha-actin expression is different in myofibroblasts and smooth muscle cells and these studies have begun to identify regulatory elements in the promoter bf SM alpha-actin that might be responsible for these differences. Therefore, the first specific aim is to identify regulatory elements within the SM alpha-actin promoter that are specific to myofibroblasts in epiretinal membranes. To address this aim we will use transgenic mice containing a SM alpha-actin promoter/LacZ transgene in which specific regulatory elements have been deleted or mutated. These mice will be mated with a transgenic mouse model in which an epiretinal membrane containing myofibroblasts forms and contracts, with subsequent retinal detachment. The second part of our long-term goal is to be able to block the contraction of myofibroblasts in the epiretinal membranes. The expression of SM alpha-actin in myofibroblasts is functionally related to the ability of these cells to generate large amounts of contractile force. Therefore, the second specific aim is to determine whether knocking out the SM alpha-actin gene will decrease or inhibit retinal detachment. Specifically we will determine the length of time it takes for retinal detachment to occur in control and SM alpha-actin-null mice. These studies will provide the basis for developing a gene therapy-based approach that can specifically target myofibroblasts in epiretinal membranes and block their generation of contractile force thereby blocking epiretinal membrane contraction and retinal detachment.

描述（由申请人提供）：随后视力丧失的视网膜脱离是与许多眼部疾病有关的主要临床问题，包括增殖性玻璃体肾上腺病（PVR）和增殖性糖尿病性视网膜病（PDR）。 手术是目前唯一可用的治疗方法，其纤维前膜形成和视网膜脱离的复发率很高。含有肌纤维细胞的平滑肌（SM）α-肌动蛋白是在PVR和PDR中形成的前膜中存在的主要细胞类型，正是这些细胞导致了导致视网膜脱离的力。这项研究的长期目标是开发一种基于基因疗法的方法，该方法靶向并阻止肌纤维细胞的收缩。该项目的第一个目的是开发肌纤维细胞特异性启动子。最近的研究表明，在肌纤维细胞和平滑肌细胞中，SMα-肌动蛋白表达的调节不同，这些研究已开始鉴定启动子BF SMα-肌动蛋白中可能导致这些差异的调节元件。因此，第一个具体目的是鉴定SMα-肌动蛋白启动子内特定于肌纤维细胞中的调节元件。为了解决此目标，我们将使用含有SMα-肌动蛋白启动子/LACZ转基因的转基因小鼠，其中已删除或突变，其中特定的调节元件已被删除或突变。这些小鼠将与转基因小鼠模型交配，其中包含肌纤维细胞和合同的前膜膜，随后的视网膜脱离。我们长期目标的第二部分是能够阻止果皮膜中肌纤维细胞的收缩。 SMα-肌动蛋白在肌纤维细胞中的表达在功能上与这些细胞产生大量收缩力的能力有关。因此，第二个特定目的是确定敲除SMα-肌动蛋白基因是否会减少或抑制视网膜脱离。具体而言，我们将确定视网膜脱离发生在对照和SMα-Actin-null小鼠中所需的时间长度。这些研究将为开发一种基于基因治疗的方法提供基础，该方法可以专门针对前膜中的肌纤维细胞，并阻止其产生的收缩力，从而阻断头上膜的收缩和视网膜脱离。