Regulation of retinal angiogenesis and vascular integrity by the oxygen sensing mechanism

通过氧传感机制调节视网膜血管生成和血管完整性

基本信息

批准号：
8964228
负责人：
Guo-Hua Fong
金额：
$ 48.71万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8964228
关键词：
Adult Affect Angiogenic Factor Animals Astrocytes Attention Binding Sites Birth Blood Circulation Blood Vessels Communication Consensus Development Diabetes Mellitus Diabetic Retinopathy Disease Down-Regulation Endothelial Cells Environment Family Feedback Figs - dietary Genes Genetic Transcription Growth Homologous Gene Hydroxylation Hyperoxia Hypoxia Hypoxia Inducible Factor In Vitro Injury Knockout Mice Lead Ligands Maintenance Methods Modeling Morphogenesis Mus Mutation Neonatal Nuclear Orphan Receptor Optic Disk Oxygen Pathway interactions Polyubiquitination Population Procollagen-Proline Dioxygenase Proteins Regulation Research Design Response Elements Retina Retinal Retinal Diseases Retinopathy of Prematurity Signal Transduction Source Stem cells Tertiary Protein Structure Testing Therapeutic Tissues Vascular Endothelial Cell angiogenesis astrocyte progenitor design extracellular in vivo insight leukemia inhibitory factor novel novel therapeutics prevent progenitor public health relevance retina blood vessel structure retinal angiogenesis theories therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Angiogenesis has been mostly studied by examining stimulation (or inhibition) of endothelial cells (ECs) by extracellular ligands, with much less attention being paid to communications between ECs and their surrounding tissue environment. In this project we will focus on how the oxygen sensing mechanism coordinates astrocytic and vascular communication during retinal vascular morphogenesis and explore its therapeutic potentials in protecting retinal microvascular integrity in two models including oxygen induced retinopathy (OIR) and diabetic retinopathy. In preliminary studies we obtained concrete evidence that nascent retinal blood vessels drive retinal astrocytic progenitors (APCs) to differentiate into mature astrocytes (mASCs) and form an astrocytic network. Specifically, we hypothesize that leukemia inhibitory factor (LIF) from retinal vascular ECs and oxygen from the circulation may act on APCs to upregulate the expression and activity of prolyl hydroxylase domain protein 2 (PHD2), which in turn catalyzes prolyl hydroxylation of HIF-a proteins, tagging them for polyubiquitination and proteasomal degradation. Furthermore, we propose that HIF-2a and Tlx (a transcription factor in the orphan nuclear receptor family) may form a positive feedback loop wherein Tlx suppresses polyubiquitination and degradation of hydroxylated HIF-2a whereas HIF-2a promotes the transcription of the Tlx gene. Thus, downregulation of HIF-2a protein abundance by PHD2 might trigger a downward spiral of both HIF-2a and Tlx levels, leading to astrocyte maturation from their progenitors. On the other hand, our studies indicate that loss of PHD2 may be targeted to help preserve retinal vascular integrity in OIR or diabetes models, likely by stabilizing HIF-2a. We will investigate these issues in three specific aims. Aim 1. Determine if LIF regulates astrocyte and vascular development through oxygen sensing mechanisms. We will evaluate in vivo if LIF upregulates Phd2 expression, promotes the differentiation of APCs (proangiogenic) to mASCs (nonangiogenic), thus suppressing retinal angiogenesis. Aim 2. Investigate if a positive feedback loop between HIF-2a and Tlx promotes APC status and retinal angiogenesis. Aim 3. Explore therapeutic potentials of the oxygen sensing pathway in mouse OIR and diabetic retinopathy models. We will determine if mASC specific PHD2 deficiency, global or EC specific LIF deficiency, or LIF antagonist protects retinal microvessels from hyperoxia or diabetes-induced injuries. In summary, these studies are designed to provide mechanistic insights into vascular and astrocyte communication and reveal novel therapeutic opportunities to treat retinopathy of the prematurity and diabetic retinopathy.

描述（由申请人提供）：血管生成主要通过检查细胞外配体对内皮细胞（EC）的刺激（或抑制）来研究，而很少关注 EC 与其周围组织环境之间的通信。重点关注氧传感机制如何在视网膜血管形态发生过程中协调星形细胞和血管通讯，并探索其在包括氧诱导视网膜病变在内的两种模型中保护视网膜微血管完整性的治疗潜力在初步研究中，我们获得了具体证据，表明新生视网膜血管驱动视网膜星形胶质细胞祖细胞 (APC) 分化为成熟星形胶质细胞 (mASC) 并形成星形胶质细胞网络。 ) ) 来自视网膜血管 EC 和循环中的氧气可能作用于 APC，上调脯氨酰羟化酶结构域的表达和活性蛋白 2 (PHD2)，反过来催化 HIF-a 蛋白的脯氨酰羟基化，标记它们进行多泛素化和蛋白酶体降解。此外，我们提出 HIF-2a 和 Tlx（孤儿核受体家族中的转录因子）可能形成一个因此，正反馈环路 Tlx 抑制羟基化 HIF-2a 的多泛素化和降解，而 HIF-2a 促进 Tlx 基因的转录。因此，PHD2 下调 HIF-2a 蛋白丰度可能会引发 HIF-2a 和 Tlx 水平的螺旋式下降，导致星形胶质细胞从其祖细胞成熟。另一方面，我们的研究表明 PHD2 的缺失可能有助于帮助星形胶质细胞成熟。可能通过稳定 HIF-2a 来保持 OIR 或糖尿病模型中的视网膜血管完整性我们将在三个具体目标中研究这些问题。确定 LIF 是否调节星形胶质细胞。我们将在体内评估 LIF 是否上调 Phd2 表达，促进 APC（促血管生成）分化为 mASC（非血管生成），从而抑制视网膜血管生成。目标 2。研究 HIF- 之间是否存在正反馈循环。 2a 和 Tlx 促进 APC 状态和视网膜血管生成目标 3. 探索氧传感通路在小鼠 OIR 和糖尿病中的治疗潜力。我们将确定 mASC 特异性 PHD2 缺陷、整体或 EC 特异性 LIF 缺陷或 LIF 拮抗剂是否可以保护视网膜微血管免受高氧或糖尿病引起的损伤。总之，这些研究旨在提供对血管和星形胶质细胞通讯的机制见解。揭示了治疗早产儿视网膜病变和糖尿病视网膜病变的新治疗机会。