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

• 批准号: 9752547
• 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
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752547
• 关键词: Adult; 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; Genes; Genetic Transcription; Growth; Homologous Gene; Hydroxylation; Hyperoxia; Hypoxia; Hypoxia Inducible Factor; In Vitro; Injury; Knockout Mice; LIF gene; Lead; Ligands; Maintenance; Methods; Modeling; Morphogenesis; Mus; Mutation; Neonatal; Nuclear Orphan Receptor; Nuclear Receptors; Optic Disk; Orphan; Oxygen; Pathway interactions; Polyubiquitination; Population; Procollagen-Proline Dioxygenase; Proteins; Regulation; Response Elements; Retina; Retinal; Retinal Diseases; Retinopathy of Prematurity; Signal Transduction; Source; Tertiary Protein Structure; Testing; Therapeutic; Tissues; Vascular Endothelial Cell; angiogenesis; astrocyte progenitor; design; extracellular; in vivo; insight; novel; novel therapeutics; preservation; prevent; progenitor; public health relevance; retina blood vessel structure; retinal angiogenesis; theories; therapeutic target; transcription factor

 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（由应用提供）：血管生成主要是通过检查（或抑制）通过细胞外配体对内皮细胞（EC）进行研究的研究，而对ECS及其周围组织环境之间的通信的关注要少得多。在该项目中，我们将重点介绍视网膜血管形态发生过程中如何协调星形细胞和血管通信，并探索其在保护视网膜微血管完整性（包括氧气诱导的视网膜疾病（OIR）和糖尿病性视网膜病）中的视网膜微血管完整性方面的治疗潜力。在初步研究中，我们获得了具体的证据表明，新生的视网膜血管驱动视网膜星形胶质细胞祖细胞（APC）分化为成熟的星形胶质细胞（MASC）并形成星形胶质细胞网络。具体而言，我们假设来自视网膜血管ECS和循环系统的白血病抑制因子（LIF）可能作用于APC，以更新prolyl羟化酶结构蛋白2（PHD2）的表达和活性，而Hif-A蛋白蛋白质蛋白质蛋白质的催化源是蛋白酶的，而蛋白酶蛋白蛋白质的蛋白酶蛋白蛋白蛋白蛋白蛋白蛋白质蛋白质却是蛋白酶的，蛋白酶的蛋白酶和蛋白酶蛋白质又可以催化。此外，我们建议HIF-2A和TLX（孤儿核受体家族中的转录因子）可能形成一个正反馈回路，其中TLX抑制了羟基化HIF-2A的多泛素化和降解HIF-2A，而HIF-2A则促进TLX基因的转录。这是PHD2对HIF-2A蛋白丰度的下调可能会引发HIF-2A和TLX水平的向下螺旋，从而导致祖细胞的星形胶质细胞成熟。另一方面，我们的研究表明，可能是通过稳定HIF-2A来帮助保留OIR或糖尿病模型中的视网膜血管完整性的损失。我们将以三个具体目标调查这些问题。目标1。确定LIF是否通过氧气敏感性机制调节星形胶质细胞和血管发育。我们将在体内评估LIF上调PHD2表达，促进APC（促血管生成）与MASC（非血管生成）的分化，从而抑制视网膜血管生成。 AIM 2。研究HIF-2A和TLX之间的阳性反馈回路是否促进了APC状态和视网膜血管生成。 AIM 3。探索小鼠OIR和糖尿病性视网膜病模型中氧气传感途径的治疗潜力。我们将确定MASC特异性PHD2缺乏，全球或EC特异性LIF缺乏症或LIF拮抗剂是否可以保护视网膜微血管免受高氧或糖尿病诱导的损伤。总而言之，这些研究旨在提供对血管和星形胶质细胞交流的机械见解，并揭示了治疗早产性和糖尿病性视网膜病变视网膜病的新型治疗机会。

项目成果

Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

• DOI: 10.1038/nm.4035
• 发表时间: 2016-02
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Cao Z;Lis R;Ginsberg M;Chavez D;Shido K;Rabbany SY;Fong GH;Sakmar TP;Rafii S;Ding BS
• 通讯作者: Ding BS

Vasculogenesis and Angiogenesis in VEGF Receptor-1 Deficient Mice.

• DOI: 10.1007/978-1-4939-2917-7_12
• 发表时间: 2015
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Ho VC;Fong GH
• 通讯作者: Fong GH

Improved vascular survival and growth in the mouse model of hindlimb ischemia by a remote signaling mechanism.

• DOI: 10.1016/j.ajpath.2013.11.032
• 发表时间: 2014-03
• 期刊: The American journal of pathology
• 作者: K. Takeda;L. Duan;Hiromi Takeda;G. Fong

Ablation of endothelial VEGFR1 improves metabolic dysfunction by inducing adipose tissue browning.

• DOI: 10.1084/jem.20171012
• 发表时间: 2018-02-05
• 期刊: The Journal of experimental medicine
• 作者: Seki T;Hosaka K;Fischer C;Lim S;Andersson P;Abe M;Iwamoto H;Gao Y;Wang X;Fong GH;Cao Y
• 通讯作者: Cao Y

Retinal Angiogenesis Regulates Astrocytic Differentiation in Neonatal Mouse Retinas by Oxygen Dependent Mechanisms.

• DOI: 10.1038/s41598-017-17962-2
• 发表时间: 2017-12-14
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Duan LJ;Pan SJ;Sato TN;Fong GH
• 通讯作者: Fong GH