Cellular and Molecular Mechanisms of Retinal Fibrosis

项目摘要 视网膜新生血管疾病，如早产儿视网膜病变和糖尿病视网膜病变是最常见的 工作年龄成年人和婴儿视力丧失的常见原因。血管内皮生长因子 血管内皮生长因子(VEGF)抑制剂改变了这些疾病的治疗方法，并改善了结果 为全世界数以百万计的患者服务。然而，新生血管的消退往往会导致沉积。 视网膜表面的纤维性疤痕。这些视网膜前纤维性疤痕会收缩，导致 视网膜表面变形或神经感觉性视网膜脱离。到目前为止，手术是唯一 可用的干预措施，往往视觉效果不佳。尽管很重要，但人们对此知之甚少 关于调节这种病理组织形成的分子机制，有 关于视网膜纤维性瘢痕组织的细胞来源的争论。主要的障碍之一是 这一领域的进展是缺乏一种健壮和可重现的小鼠模型来研究和操作Pre 视网膜纤维化，以破译调节这一过程的关键细胞和分子机制 进程。我们开发了一种新的早产儿严重视网膜病变小鼠模型 缺氧后视网膜前纤维化导致新生血管。利用组织学和单细胞 测序，我们的初步数据表明，视网膜前纤维性瘢痕是由周细胞引起的 新生血管形成后I型胶原表达上调。在这里，我们建议进一步了解 通过描述和操纵这一新的模型来研究视网膜前瘢痕形成的机制。第一, 我们将充分描述这一模型的特点，检测纤维化瘢痕形成、血管-血管形成的时间过程。 阻塞、新生血管、视网膜炎症和视功能。第二，使用世系追踪 和单细胞测序，我们将确定关键的I型胶原产生细胞的身份。第三, 我们建议验证这样的假设，即周细胞中转化生长因子β信号的激活是Pre-Pre的关键驱动因素。 视网膜纤维化。我们理解视网膜纤维化的细胞和分子起源的目标是 开发新的治疗方法以防止晚期缺血性视网膜病变的牵引致盲。

PROJECT ABSTRACT Retinal neovascular disorders, such as retinopathy of prematurity and diabetic retinopathy, are the most common causes of vision loss of working age adults and infants. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders and resulted in improved outcomes for millions of patients worldwide. However, regression of neovascularization often leads to deposition of a fibrotic scar on the surface of the retina. These pre-retinal fibrotic scars can contract, resulting in distortion of the retinal surface or detachment of the neurosensory retina. To date, surgery is the only available intervention, often with poor visual outcomes. Despite the importance, very little is known about the molecular mechanisms that regulate the formation of this pathological tissue, and there is debate on the cellular source of fibrotic scar tissue in the retina. One of the main roadblocks for making progress in this field is the lack of a robust and reproducible mouse model to study and manipulate pre- retinal fibrosis, in order to decipher the key cellular and molecular mechanisms that regulate this process. We have developed a novel mouse model of severe retinopathy of prematurity that develops pre-retinal fibrosis subsequent to hypoxia driven neovascularization. Using histology and single cell sequencing, our preliminary data indicates that the pre-retinal fibrotic scar results from pericytes that upregulate collagen I expression following neovascularization. Here, we propose to further understand the mechanism of pre-retinal scar formation by characterizing and manipulating this novel model. First, we will fully characterize this model examining the time course of fibrotic scar formation, vaso- obliteration, neovascularization, retinal inflammation, and visual function. Second, using lineage tracing and single cell sequencing we will determine the identity the critical collagen I producing cells. Third, we propose to test the hypothesis that activation of TGFβ signaling in pericytes is the key driver of pre- retinal fibrosis. Our goal in understanding the cellular and molecular origin of retinal fibrosis is to develop novel therapeutics to prevent blindness from traction in advanced ischemic retinopathies.